CJi6 MoL. wt: 54 · PDF fileCJi6 MoL. wt: 54.09CH2=CH-CH=CH2 1.1.2 Chemical and physical properties (a) ... 0.6211 g/ml at 20 °e/liquefied (Kirshenbaum, ... di-n-butylamine,

1,3-BUTADIENE

This substance was considered by previous working groups in June 1985 (IARC, 1986a;see also correction, IARC, 1987a) and March 1987 (IARC, 1987b). Since that time, new datahave become available, and these have been incorporated into the monograph and takeninto consideration in the present evaluation.

1. Exposure data

1.1 Chemical and physical data

1.1.1 Synonyms, structural and molecular data

Chem. Abstr. Serv Reg. No.: 106-99-0Chem. Abstr. Name: 1,3-ButadieneIUPAC Systematic Name: 1,3-ButadieneSynonyms: Biethylene; bivinyl; butadiene; buta-l,3-diene; æ;y-butadiene; trans-butadiene; divinyl; eryhrene; pyrrolylene; vinylethylene

CH2=CH-CH=CH2CJi6 MoL. wt: 54.091.1.2 Chemical and physical properties

(a) Description: Colourless gas with mildly aromatic odour; easily liquefied (Sax &Lewis, 1987)

(b) Boilng-point: -4.4 °C (Weast, 1989)

(c) Melting-point: -108.9 °C (Weast, 1989)(d) Density: 0.6211 g/ml at 20 °e/liquefied (Kirshenbaum, 1978; Verschueren, 1983)(e) Spectroscopy data: Ultraviolet (Grasselli & Ritchey, 1975), infrared (Sadtler

Research Laboratories, 1980; prism (893tZ, grating (36758)), nuclear magneticresonance and mass spectral data (US National Institutes of Health/EnvironmentalProtection Agency ehemIcal Information System, 1983) have been reported.

if Solubilty: Very slightly soluble in water (735 mg/l at 20°C); soluble in ethanol,diethyl ether and organIc solvents (Verschueren, 1983; Sax & Lewis, 1987;Budavari, 1989)

(g) Volatilty: Vapour pressure, 1790 mm Hg (239 kPa) at 20°C (Santodonato, 1985);relative vapour density (air = 1), 1.87 (Verschueren, 1983)

aSpectrum number in SadtIer compilation

-237-

238 lARe MONOGRAPHS VOLUME 54

(h) Stability: Flash-point, -76°C (Sax & Lewis, 1987); slowly dimerizes to 4-vinyl-l-cycIohexene (US Occupational Safety and Health Administration, 1990); may formperoxides upon exposure to air (Kirshenbaum, 1978)

(í) Reactivity: Polymerizes readily, particularly if oxygen is present (Sax & Lewis, 1987)(j) Conversion factorb: mg/m3 = 2.21 x ppm

1.1.3 Technical products and impurities

1,3-Butadiene is available commercially as a Iiquefied gas under pressure in severalgrades of purity, incIuding a special purity or instrument grade of 99.4-99.5 mol% purity, aresearch grade of99.86 mol% purity, a technical-commercial grade of98 mol% purity and arubber grade (Santodonato, 1985). AnalyticaI, polymer, rubber and liquid grades (AldrichChemical Co., 1990; Kuney, 1990) range in minimal purity from 99.0 to 99.5%, with thefollowing tyical impurities: 1,2-butadiene, acetaldehyde (see IARC, 1987b), acetylenes(alpha, viny!), propadiene, butadiene di mer (4-vinylcycIohexene, see IARC, 1 986b), pero-xides, sulfur and Cs hydrocarbons. Oxidation/polymerization of 1,3-butadiene is inhibited byaddition of hydroquinone, di-n-butylamine, tert-butylcatechol, aliphatic mercaptans orortho-dihydroxybenzene (Exxon Chemical Co., 1973; Kirshenbaum, 1978; Lyondell Petro-chemical Co., 1988; Budavari, 1989).

Crude 1,3-butadiene is also available from many producers for use as a feedstock. Suchgrades contain a minimum of 36-65% 1,3-butadiene, with specifications tyically given foracetylenes, C3 compounds and lighter hydrocarbons, Cs compounds and heavier, peroxides,carbonyl compounds, sulfur and organic chlorides. Inhibitors (e.g., tert-butylcatechol, 50-200 ppm) are also added (Vista Chemical Co., 1985; Union Carbide Corp., 1987).

1. 1.4 Analysis

Selected methods for the analysis of 1,3-butadiene In various matrices are listed inTable 1 (methods used previously are given in section 1.3.2).

The specificity and the detection limit of methods for determining simple, smallmolecules present in packaging materials which migrate into packaged goods have beendiscussed (Vogt, 1988). 1,3-Butadiene can be determined in plastic polymers, foods and foodsimulants by chromatographic methods.

Several gas detector tubes are used in conjunction with common colorimetric reactionsto detect 1,3-butadiene. The reactions include the reduction of chromate or di

chromate tochromous ion and the reduction of ammonium molybdate and palladium sulfate tomolybdenum blue (Saltzman & Harman, 1989).

1.2 Production and use

1.2.1 Production

1,3-Butadiene was first produced in 1886 by the pyrolysis of petroleum hydrocarbons(Kirshenbaum, 1978). Commercial production started in the 1930s (Kosaric et a/., 1987).

bCalculated from: mg/m3 = (molecular weight/24.45) X ppm, assuming normal temperature (250C) and

pressure (760 mm Hg (101.3 kPaJ)

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1,3-BUTADIENE 239

Table 1. Methods for the analysis of l,3-butadiene

Sample Sample preparation Assay Limit of Referencematri procedure detection

Ai Collect on solid sorbent tube; desorb with GC/FID 0.04 mg/m3 ElIer (1987)

dichloromethane; chil in iceCollect on sol id sorbent tube of charcoal GC/FID 0.35 mg/m3 Hendricks &coated with tert-butylcatechol; desorb with Schultz (1986)carbn disulfideInject sample into GC using a temperature- GC/FID 0.01 ppm by Locke et al. (1987)programmed, fused-silica, porous layer, open volumetubular Ali03/KCI column (0.01 iil/l)Assay directly Fr-IR 5ppm Harman (1987)

(10 mg/m3)Plastics, Dissolve in ortho-dichlorobenzene; inject GC/FID 2-20 iig/kg US Foo and Drug

liquid headspace sample Administrationfoos (1987)

Soli Cut or mash sample; inject headspace GC/FID 2-20 iig/kg US Foo and Drugfoos sample Administration

(1987)

Abbreviations: Fr-IR, Fourier transform-infrared absorption spectroscopy; GC, gas chromatograph; GC/FID, gas chromatographylfame ionization detection

1,3-Butadiene has been produced commercially by three processes: catalytic dehydro-genation of n-butane and n-butene (the Houdry process), oxidative dehydrogenation ofn-butene (the Oxo-D or O-X-D process) and recovery from the C4 co-product (by-product)stream from the steam cracking process used to manufacture ethylene (the ethyleneco-product process). AIl three processes involve the production of 1,3-butadiene from a C4hydrocarbon stream, and solvent extraction and extractive distilation are used in aIl three tofurther concentrate the 1,3-butadiene. There has recently been a shift to the use of cheaper,heavier feedstocks for ethylene production, with a concomitant increase in the volume ofco-product containing 1,3-butadiene (Krishnan & eorwn, 1987). The ethylene co-productprocess accounts for approximately 95 % of US and 85 % of worldwide production (Morrow,1990).

The production of 1,3-butadiene is thus a two-stage process: (i) production of a e4 co-product during ethylene manufacture and (ii) recovery of 1,3-butadiene from the co-product.The first stage consists of cracking a hydrocarbon such as naphtha to produce ethylene as theprimary product and a co-product stream composed of e4 hydrocarbons. The amount of 1,3-butadiene in the co-product depends on the feedstock used and the severity of the crackingprocess:the heavier the feedstock and the more severe the cracking, the more 1,3-butadieneis produced. The 1,3-butadiene content of the co-product C4 stream is 20-70%; the C4 feedstreams are usually blended with a feed stream containing 40-50% 1,3-butadiene for pro-cessing. ln the extraction plants, sol vents such as dimethylformamide, acetonitrile, furfural,dimethylacetamide and methylpyrrolidone are used (US Occupational Safety and HealthAdministration, 1990) to alter the volatilty of components in a fractional distilation

240 lARe MONOGRAHS VOLUME 54

selectively and to produce a high purity (? 99.0%) 1,3-butadiene mono

mer (Krishnan &Corwn, 1987).ln 1987, worldwide production of 1,3-butadiene was approximately 5.5 milion tonnes

(Morrow, 1990). A more detailed accounting of the production of 1,3-butadiene in severalcountries in 1980-90 is presented in Table 2. Global 1,3-butadiene consumption in 1987 wasestimated at 5.5 milion tonnes, 1.5 milion tonnes ofwhich were used in the USA As in mostyears, the US demand exceeded its supply, so approximately 227 thousand tonnes of1,3-butadiene monomer were imported in 1987 (Morrow, 1990).

Table 2. Trends in production of l,3-butadiene in several countries (thousand tonnes)

Country 1980 1981 1982 1983 1984 1985 1986 1987 1988 1989 199Canada NA 126 118 133 127 132 146 167 182 175 192France 259 26 258 281 303 288 291 307 335 329 281Gennanya NA NA 579 717 754 84 683 701 761 717 771Italy 183 166 159 195 181 NA NA NA NA NA NAJapan 574 518 522 556 627 639 656 707 780 827 827Mexico 17 12 15 19 20 18 18 21 12 NA NAUnited Kingdom 192 207 228 237 259 297 192 231 239 226 195USAb 1270 1356 869 1068 1113 1062 1156 1329 1437 1417 1435From Anon. (1984, 1986, 1988, 1991b); NA, not availableIligures prior to 199 are for western Germany onlybRubber grade

Information available in 1988 indicated that 1,3-butadiene was produced by ninecompanies in Germany, eight in Japan, four in the United Kingdom and in Brazil, three inFrance, two in Australia, Belgium, Canada, the NetherIands and Spain, and one each inArgentina, Austria, Bulgaria, China, Czechoslovakia, Finland, India, Italy, Mexico, Poland,Saudi Arabia, Singapore, Taiwan and Yugoslavia (ChemicaJ Information Servces, 1988). Itwas produced by eight companies in the USA in 1991 (Anon., 1991a).

1.2.2 Use

1,3-Butadiene is used principaIJy as a monomer in the manufacture of a wide range ofpolymers and copolymers. Polymerization of styene and 1,3-butadiene yields styene-butadiene rubber, the largest single use of butadiene; almost 80% of the styene-butadienerubber produced is used in tyes and tye products. Polymerization of 1,3-butadiene

produces polybutadiene, almost aIl of which used for car and bus tyes. Nitrile rubber isproduced by copolymerizing 1,3-butadiene and acrylonitrile; it is used in hoses, gaskets,seals, latexes, adhesives and footwear. Aciylonitrile-butadiene-styene resins are graft ter-polymers ofpolybutadiene on a styene-aciylonitrile copolymer; they are used in automotiveparts, pipes, appliances, business machines and telephones. Styene-butadiene latexes aresuspensions of particles or globules of the elastomer in water and are used in paper coatingsand paints and as carpet backing (Santodonato, 1985; US OccupationaJ Safety and HealthAdministration, 1990).

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1,3-BUTADIENE 241

1,3-Butadiene is used as a chemical intermediate in the production of a number ofimportant chemicals. Neoprene is made by chlorinating 1,3-butadiene and treating theresultant chloroprene with sodium hydroxide; two-thirds of the neoprene produced is usedfor industrial and automotive rubber goods. Adiponitrile is produced by chlorinating1,3-butadiene and cyanating the product to 1,4-dicyanobutene, which is then reduced toadiponitrile; this is converted to hexamethylenediamine for the production of Nylon 66.l,4-Hexadiene, made by reacting 1,3-butadiene with ethylene, is used as a monomer forethylene-propylene terpolymer. Sulfolane, produced by reacting sulfur dioxide and1,3-butadiene and dehydrogenating the product, is a valuable solvent for extraction. 1,5,9-Cyclodecatriene is produced by trimerizing 1,3-butadiene and is used for the production ofvarious nylon fibres and resins. Sorne other nonpolymer applications include manufacture ofagricultural fungicides (cap tan and captafol) and anthraquinone dyes (Santodonato, 1985;US Occupational Safety and Health Administration, 1990).

ln 1990, 1,3-butadiene was used in the USA for: styene-butadiene rubber (30%), poly-butadiene rubber (20%), adiponitrile/hexamethylenediamine (15%), styene-butadienelatex (10%), neoprene rubber (5%), acrylonitrile-butadiene-styene resins (5%), exports(4%), nitrile rubber (3%) and other (including specialty polymers) (8%) (Anon., 1991a).

(For more detailed discussions of the production and use of 1,3-butadiene, see Miler,1978; Leviton, 1983; Greek, 1984.)

1.3 Occurrence

1.3.1 Naturaloccurrence

1,3-Butadiene is not known to occur as a natural product (Santodonato, 1985).

1.3.2 Occupational exposure

On the basis of a National Occupational Exposure Survey, the US National Institute forOccupational Safety and Health (1990) estimated that 52 000 workers were potentiallyexposed to 1,3-butadiene in the USA in 1981-83. Potential exposure to 1,3-butadiene canoccur in the following industrial activities: petroleum refining and related operations(production of C4 fractions containing 1,3-butadiene, production and distribution of gaso-line), production of purified 1,3-butadiene monomer, production of various 1,3-butadiene-based rubber and plastics polymers and other derivatives, and the rubber and plasticsproducts manufacturing industry (production of tyes, hoses and a variety of mouldedobjects).

ln the descriptions below, the accuracy of the levels of exposure to 1,3-butadiene mayhave been affected by inabilty to distinguish between 1,3-butadiene and other C4 com-pounds, low desorption effciency at low concentrations, possible sample breakthrough incharcoal tubes and possible loss during storage, in methods used until the mid-1980s(Lunsford et al., 1990). No data are available on levels of exposure to 1,3-butadiene beforethe 1970s, when different processes and working conditions (e.g., during the Second WorldWar) would have resulted in exposure conditions different from those now prevalent indeveloped countres.


(a) Petroleum refining and production of crude 1,3-butadiene

Gasoline contains a small percentage of 1,3-butadiene, and exposures of workers invarious job groups in the production and distribution of gasoline are shown in Table 3. Thble

4 shows the exposures since 1984 of workers in different areas of petroleum refineries andpetrochemical facilties where crude 1,3-butadiene is produced (usually a C4 stream obtainedas a by-product of ethylene production).

Table 3. Personal exposures (mg/m3) to 1,3-butadiene associated withgasoline during 198485 in 13 European countries

Activity Mean Range Expsureduration(IA)

Production on-site (refining) 0.3 ND-lIA 8 hProduction off-site (refining) 0.1 ND- 1.6 8 hLoading ships (closed system) 6.4 ND-21.0 8 hLoading ships (open system) 1.1 ND-4.2 8 hLoading barges 2.6 ND-15.2 8 hJ ettyan 2.6 ND-15.9 8 hBulk loading road tankers

Top loading -: 1 h 1.4 ND-32.3 -: 1 hTop loading :: 1 h 004 ND-4.7 8 hBottom loading -: 1 h 0.2 ND-3.0 -: 1 hBottom loading :: 1 h 0.4 ND-14.1 8 h

Road tanker delivery (bulk plant to service station) NDRailcar top loading 0.6 ND-6.2 8 hDrumming NDServce station attendant (dispensing fuel) 0.3 ND-LI 8 hSelf-service station (fillng tank) 1.6 ND-10.6 2 min

From CONCAWE (1987); ND, not detected; 1WA time-weighted average

Table 4. Mean 8-h time-weighted average concentrations of1,3-butadiene to which workers in ditTerentjobs in petroleumrefineries and petrochemical facilties have been exposedsince 1984

Job area No. of Mean" Rangefacilties

ppm mg/m3 ppm mg/m3

Production 7 0.24 0.53 0.008-2.0 0.02-4.4Maintenance 6 0.11 0.24 0.02-0.37 0.04.82Distribution 1 2.9 64.1Laboratory 4 0.18 0.40 0.07-0.4 0.16-.88

From Heiden Assotes (1987)"Weighted by number of expsed workers

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1,3-BUTADIENE 243

(h) Monomer production

Detailed industrial hygiene surveys were conducted by the US National Institute forOccupational Safety and Health in 1985 in four of 10 US facilities where 1,3-butadiene wasproduced by solvent extraction of C4 fractions originating as ethylene co-product streams(Krishnan et al., 1987). Levels of 1,3-butadiene to which workers in various job categorieswere exposed are summarized in Table 5. Jobs that require workers to handle or transportcontainers, such as voiding sample cylinders or loading and unloading tank trucks or rail cars,present the greatest potential exposure. Geometric means of full-shift exposure levels forother job categories were below 1 ppm (2.2 mg/m3). Short-term samples showed that su chactivities as open-Ioop sampling and cylinder voiding were associated with peak exposures of100 ppm (220 mg/m3). Full-shift area samples indicated that ambient concentrations of1,3-butadiene were greatest in the railcar terminaIs (geometric me an, 1.77 (3.4 mg/m3)) andin the tank storage farm (2.12 ppm (3.4 and 4.7 mg/m3)).

Table 5. Full-shift, time-weighted average exposure levels iD personal breathing-zone samples at four US 1,3-butadiene monomer production facilties, 1985

Job categoiy No. of Exposure level (ppm (mg/m3Dsamples

Arthmetie Geometrie Rangemean mean

Process teehnieian 10 0.45 (1.0) 0.09 (0.20) ~ 0.02-1.87 (~ 0.04-4.1)Control room

Process teehnieian 28 2.23 (4.9) 0.64 (l.4) ~ 0.08-34.9 (~ 0.18-77.1)Process areaLoading area

Railcar 9 14.64 (32.4) 1.00 (2.2) 0.12-123.57 (0.27-273.1)Thnk truek 3 2.65 (5.9) 1.02 (2.3) 0.08-5.46 (0.18-12.1)Thnk farm 5 0.44 (0.97) 0.20 (0.44) ~ 0.04-1.53 (~ 0.09-3.4)

Laboratoiy teehnieian 29 1.06 (2.3) 0.40 (0.88) 0.03-6.31 (0.07-14.0)Cylinder voiding 3 125.52 (277.4) 7.46 (16.5) 0.42-373.54 (0.93-825.5)

From Krishnan et al. (1987)

ln 1984, the US Chemical Manufacturers' Association obtained data on personalexposure to 1,3-butadiene before 1984 from 13 monomer-producing companies, catego-rized broadly by job tye (Table 6). These data were collected by an older method andprovide a historical perspective on the data reported in Table 5. The highest exposures werein the maintenance and distribution jobs. Out of a total of 1287 samples, 91 % were less th anor equal to 10 ppm (22.1 mg/m3) and 68% were less th an or equal to 5 ppm (11.1 mg/m3).Factors that limit generalization of these data are unspecified sampling and analytical

techniques, lack of detailed job descriptions and different or uDspecified average times ofsampling (JACA eorp., 1987).

Monitoring in a Finnish plant generally indicated ambient air levels of less than 10 ppm(22.1 mg/m3) at different sites (33 samples; mean sampling time, 5.3 h). ln personal samplesfor 16 process workers, the concentration ranged from -c 0.1 to 477 ppm (-c 0.22-1054.2

t

Table 6. Time-weighted average exposure to 1,3-butadiene in 13 US monomer production plants before 1984 -~

Job area No. of Expsure (ppm (mg/m3)) f3samples ~

0.00-5.00 5.01-10.00 10.01-25.00 25.01-50.00 50.01-100.00 :; 100.000Z

(0-11.05) (11.07-22.12) (22.12- 55.25) ( 55.27-110.50) ( 110.52-221.23) (:; 221.23) 0aNo. % No. % No. % No. % No. % No. % ~

""Production 562 446 79.4 111 19.7 5 0.9 ::r.Maintenance 329 247 75.1 47 14.3 35 10.6

dSupervsoiy 64 60 93.8 4 6.2Distribution 20 60 29.1 121 58.7 16 7.8 5 2.4 2 1.0 2 1.0 ELaboratoiy 126 58 46.0 68 54.0 ~Total 1287 871 67.8 304 23.6 68 5.3 40 3.1 2 0.1 2 0.1

trVI.¡

From JACA Corp. (1987)

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1,3-BUTADIENE 245

mg/m3) (mean, 11.5 ppm (25.4 mg/m3); median, -: 0.1 ppm (~ 0.22 mg/m3); 46 samples;

mean sampling time, 2.5 h). The highest concentrations were measured during samplecollection. Protective clothing and respirators were used during this operation(Arbetsmiljöfonden, 1991).

Potential exposure in the monomer industry other than to 1,3-butadiene includesextraction solvents and components of the e4 feedstock. Extraction solvents differ amongfacilities; sorne common ones are dimethylformamide, dimethylacetamide, acetonitrile,ß-methoxyropylnitrile (Fajen, 1985a), furfral and cuprous ammonium acetate (US Occu-pational Safety and Health Administration, 1990). Stabilizers are commonly used to preventformation of peroxides in air and polymerization (see p. 238). No information was availableon these other exposures, or on exposures to chemicals other than 1,3-butadiene that areproduced in sorne facilities, such as butylenes, ethylene, propylene, polyethylene and poly-propylene resins, methyl-tert-butyl ether and aromatic hydrocarbons (Fajen, 1985b,c).

(c) Production of polymers and denvatives

Detailed industrial hygiene surveys were conducted in 1986 in five of 17 US facilitieswhere 1,3-butadiene was used to produce styene-butadiene rubber, nitrile-butadienerubber, polybutadiene rubber, neoprene and adiponitrile (Fajen, 1988). Levels of 1,3-butadiene to which workers in various job categories were exposed are summarized in Table7. Pro cess technicians in unloading, the tank farm, purification, polymerization and reaction,laboratoiy technicians and maintenance technicians were exposed to the highest levels.Short-term sampling showed that activities su ch as sampling a barge and laboratory workwere associated with peak exposures to more than 100 ppm (221 mg/m3). Full-shift areasampling indicated that geometric mean ambient concentrations of 1,3-butadiene were lessthan 0.5 ppm (1.1 mg/m3) and usually less than 0.1 ppm (0.22 mg/m3) in all locations at thefive plants.

Eight-hour time-weighted average (TWA) exposures to 1,3-butadiene in the polymerindustiy were obtained by personal sampling in Il North American sythetic rubber plants in1978-84 and reported by the International Institute of Synthetic Rubber Producers in 1984(JACA Corp., 1987) (Table 8). The highest exposures were found for tank car loaders (15% ofexposures, :; 10 ppm ( :; 22.1 mg/m3)), reactor operators (18% of exposures, :; 10 ppm) andlaboratory technicians (6% of exposures, :; 10 ppm). Sampling and analytical techniques

and job descriptions were not available.

Other data on levels of exposure to 1,3-butadiene have been collected during healthsurveys and epidemiological studies (Table 9). ln a US styene-butadiene rubber manu-facturing plant in 1979, the only two departments in which levels were greater than 10 ppm(22.1 mg/m3) were tank farm (53.4 ppm (118 mg/m3)) and maintenance (20.7 ppm (45.8mg/m3)) (eheckoway & Willams, 1982). ln samples taken at one of two US styene-butadiene rubber plants in 1976, levels above 100 ppm (221 mg/m3) were encountered bytechnical servces personnel (114.6 ppm (253.3 mg/m3)) and an instrument man (174.1 ppm

(384.78 mg/m3)) (Meinhardt et al., 1978). Overall mean 8-h TWA exposure levels differedconsiderably between the two plants, however: 1.24 ppm (2.74 mg/m3) in one plant and 13.5ppm (29.84 mg/m3) in the other (Meinhardt et al., 1982).


Table 7. FuIl-shift time-weighted average exposure levels in personal breathing-zonesamples at five US plants producing 1,3-butadiene-based polymers and derivatives,1986

Job categoiy No. of Expsure level (ppm (mg/m3))samples

Arthmetie Geometrie Rangemean mean

Process teehnieianUnloading area 2 14.6 (32.27) 4.69 (10.37) 0.770-28.5 (1.7-63.0)Thnk fann 31 2.08 (4.60) 0.270 (0.60) c: 0.0023.7 (c: 0.01-52.4)

Puriication 18 7.80 (17.24) 6.10 (13.48) 1.33-24.1 (3.0-53.3)Polymerition or reaetion 81 0.414 (0.92) 0.062 (0.14) c: 0.0011.3 (c: 0.01-25.0)

Solutions and coagulation 33 0.048 (0.11) 0.029 (0.06) c: 0.005-0.169 (c: 0.01-0.4)

Crumbing and diying 35 0.033 (0.07) 0.023 (0.05) c: 0.005-0.116 (c: 0.01-0.26)

Paekaging 79 0.036 (0.08) 0.022 (0.05) c: 0.005-0.154 (c: 0.01-0.34)

Warehouse 20 0.020 (0.04) 0.010 (0.02) c: 0.005-0.068 (c: 0.01-0.15)

Control room 6 0.030 (0.07) 0.019 (0.04) c: 0.012-0.070 (c: 0.03-0.16)

Laboratoiy technician 54 2.27 (5.02) 0.213 (0.47) c: 0.0037.4 (c: 0.01-82.65)

Maintenance technician 72 1.37 (3.02) 0.122 (0.27) c: 0.00-43.2 (c: 0.01-95.47)

Utilities operator 6 0.118 (0.26) 0.054 (0.12) c: 0.00-0.304 (c: 0.01-0.67)

From Fajen (1988)

The manufacture of butadiene-based polymers and butadiene derivatives implies poten-tial occupational exposure to a number of other chemical agents, which varies according toproduct and process. These include other monomers (styene (see IARC, 1987b), acrylo-nitrile (see IARC, 1987b), chloroprene (see IARC, 1979)), solvents, additives (e.g., acti-vators, antioxidants, modifiers), catalysts, mineraI oils (see lARe, 1987b), carbon black (seeIARC, 1987b), chlorine, inorganic acids and caustic solution (Fajen, 1986a,b; Roberts, 1986).Styene, benzene (see IARC, 1 987b) and toluene (see IARC, 1989) were measured in variousdepartments of a US styene-butadiene rubber manufacturing plant in 1979: mean 8-h TW Alevels of styene were below 2 ppm (8.4 mg/m3), except for tank farm workers (13.7 ppm (57.5mg/m3), 8 samples); mean benzene levels did not exceed 0.1 ppm (0.3 mg/m3), and those oftoluene did not exceed 0.9 ppm (3.4 mg/m3) (eheckoway & Wiliams, 1982). Meinhardtet al.(1982) reported that the me an 8-h TWA levels of styene were 0.94 ppm (3.9 mg/m3) (55samples) and 1.99 ppm (8.4 mg/m3) (35 samples) in two styene-butadiene rubber manu-facturingplants in 1977; the average benzene level measured in one of the plants was 0.1 ppm(0.3 mg/m3) (3 samples). Average levels of styene, toluene, benzene, vinyl cyclohexene andcyclooctadiene were reported to be lower than 1 ppm in another styene-butadiene rubberplant in 1977 (Burroughs, 1977).

(d) Rubber and plastics products manufacturing industriesUnreacted 1,3-butadiene was detected as only a trace (0.04-0.2 ng/mg) in 15 of37 bulk

samples of polymers and other chemicals synthesized from 1,3-butadiene and analysed in1985-86. Only two samples contained measurable amounts of 1,3-butadiene: tetrahydro-phthalic anhydride (53 ng/mg) and vinyl pyridine latex (16.5 ng/mg) (JACA eorp., 1987).

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Table 8. Time-weighted average exposures to l,3-butadiene in 11 North American plants producing synthetic rubber, 1978-84

Occpation al No. of Exure (ppm (mglm3J)group samples -

0.005.00 5.01-10.00 10.01-25.00 25.01-50.00 50.01-100.00 100.01-20.00 20.01-500.00 500.01-100.00(0-1105) (1107-22121 (2212-55.25) (55.27-110.50) ¡ 110.52-22123) (221.23-420.00) ¡442.02-1io5.oo) (1105.02-2210.00)

No. % No. % No. % No. % No. % No. % No. % No. %

Tank car !oader 102 78 76.5 9 8.8 9 8.8 4 3.9 2 2.0Vess! cleaner 214 199 93 9 4.2 4 1.9 2 0.9Charge solution 89 83 93.2 3 3.4 2 23 1 1.

make-up ..WReactor operator 190 133 70 22 116 14 7.4 7 3.7 7 3.7 5 26 1 0.5 J 1 0.5 1tlRecovery operator 108 100 926 5 4.6 2 1.9 1 0.9 C

Coagulation 185 173 93.5 9 4.9 2 1.1 1 0.5 ~operatorVDryer operator 85 84 98.8 1 1.2 -t'Ba1er and packager 167 164 98.2 2 1.2 1 0.6

æWarehouseman 22 22 100

Laboratory 116 103 88.8 6 5.2 6 5.2 1 0.9technician

Maintenance 262 241 920 12 4.6 4 1.5 2 0.8 3 1.technician

Supervr 123 11 90.2 6 4.9 6 4.9

Waste treatment 9 9 100operator

Total 1672 1500 89.7 84 5.0 48 29 20 1.2 13 0.78 5 0.30 i 0.06 i 0.06

From JACA Corp. (1987)

N.¡-.


Table 9. Mean 8-h time-weighted average concentrations of l,3-butadiene measuredin two US styrene-butadiene rubber manufacturing plants

Job classification or department No. of Concentration Year of Referencesamples sampling

ppm mg/m3

Instrument man 3 58.62 129.55 1976 Meinhardt et al.Technical services personnel 12 19.85 43.87 (1978)Head production operator 5 15.50 34.26Carpenter 4 7.80 17.24Production operator 24 3.30 7.29Maintenance mechanic 17 3.15 6.96Common labourer 17 1.52 3.36Production foreman 1 1.6 2.56Operator helper 3 0.79 1.75Pipefitter 8 0.74 1.64Electrician 5 0.22 0.49

Thnk farm 8 20.03 44.3 1979 Checkoway &Maintenance 52 0.97 2.14 Wiliams (1982)Reactor and recovery 28 0.77 1.7Solution 12 0.59 1.3Factory servce 56 0.37 0.82Shipping and receiving 2 0.08 0.18Storeroom 1 0.08 0.18

Detailed industrial hygiene surveys were conducted in 1984-87 in a US rubber tye plant anda US industrial hose plant where styene-butadiene rubber, polybutadiene and aciylo-nitrile-butadiene rubber were processed. No 1,3-butadiene was detected in any of a total of124 personal full-shift samples from workers in the following job categories, which wereidentified as involving potential exposure to 1,3-butadiene: Banbury operators, miloperators, extruder operators, curing operators, conveyer opera tors, calendering operators,wire winders, tube machine operators, tye builders and tye repair and buffer workers (Fajen

et al., 1990).

Measurements ta ken in 1978 and 1979 in personal 8-h samples in companies whereacrylonitrile-butadiene-styene moulding operations were conducted showed levels of~ 0.05-1.9 mg/m3 (Burroughs, 1979; Belanger & Elesh, 1980; Ruhe & Jannerfeldt, 1980). lna polybutadiene rubber warehouse, levels of 0.003 ppm (0.007 mg/m3) were found in areasamples; area and personal samples taken in tye plants contained 0.007-0.05 ppm (0.016-0.11 mg/m3) (Rubber Manufacturers' Asociation, 1984). ln a US tye and tube manufac-turing plant in 1975, a cutter man/Banbury operator was reported to have been exposed to1,3-butadiene at 2.1 ppm (4.6 mg/m3)

(personal 6-h sample) (Ropert, 1976).

Occupational exposures to many other agents in the rubber goods manufacturing

industr were reviewed in a previous monograph (lARe, 1982).

1,3- BUTAD IENE 249

1.3.3 Air

ln 1989, total emissions of 1,3-butadiene to the air in the USA were estimated atapproximately 2512 tonnes from 158 locations; total land releases were estimated at 6.7tonnes (US National Library of Medicine, 1991).

Data on annual emissions of 1,3-butadiene from US facilities producing 1,3-butadiene,polybutadiene, neoprene/chloroprene and styene-butadiene rubber and from miscella-neous facilities where 1,3-butadiene was used were collected in 1984 by the US Environ-mental Protection Agency. Data on episodic emissions were collected from most of the samefacilities in 1985-86 (US Environmental Protection Agency, 1987; Mullins, 1990). Averageannual emissions, the average rates and durations of episodic emissions and the highest ratesfor specific tyes of emissions are presented in Table 10.

Table 10. 1,3-Butadiene emissions from US manufacturing facilties in 1984-86

Activity of facility No. of Total emissions Episodic emissions (1986)facilities (tonnes/year)

Average Range Average rate Highest average Average(kg/min) rate (kg/min) duration (min)

1,3-Butadiene lOa 135.9 6.8-752 355 1600b 2170production 1100cPolybutadiene 7 57.4 22.1-176 24 B1.4c 7.5production 24.0dChloroprene/- 2 10, 32.2 2.9 1B1b 38.8neoprene productionStyrene-butadiene 17 49.3 0.9-145 3.9 9.ge 49.6rubber production 9.2cUsing 1,3-butadiene Il! 63.5 2.2-350 NR NR NR

From US Environmental Protection Agency (1987); NR, not reportedOEpisodic emissions reported for eight facilitiesbpressure relief dischargesc Accidental liquid releases

dJquipment openingseAccidental gas releases

fEpisodic emissions reported for five facilities

Few data are available on levels of 1,3-butadiene in ambient air; reported concen-trations in urban air generally range from less than 1 to 10 ppb (2-22 llg/m3) (Neligan, 1962;Cote & Bayard, 1990). ln the USA, combined levels of 1,3-butadiene and 2-butene were5.9-24.4 ppb (0.01-0.05 mg/m3) in 1978 in Tulsa, OK (Arnts & Meeks, 1981), and 0-0.019ppm (0-0.042 mg/m3) in 1973-74 in Houston, TX (Siddiqi & Worley, 1977). Levels of1,3-butadiene were 0.004 mg/m3 in Denver, CO, and ~ 0.001-0.028 mg/m3 in various citiesin Texas (Hunt et al., 1984); urban air in Los Angeles and Riverside, eA contained levels ashigh as 9 ppb (0.02 mg/m3) (Parsons & Wilkins, 1976).


1,3-Butadiene was found in 32% of 24-h ambient air samples taken in 19 US cities in1987-88, at a mean concentration of 1.39 ¡.g/m3 (range, 0.11-6.94) (US EnvironmentalProtection Agency, 1989).

1.3.4 Uiter1,3-Butadiene has been detected in drinking-water in the USA (US Environmental

Protection Agency, 1978; Kraybil, 1980). Total releases to ambient water in 1989 wereestimated to be 65 tonnes (US National Library of Medicine, 1991).

1.3.5 Food

Levels of -( 0.2 ¡.g/kg 1,3-butadiene were found in retail soft margarine; the plastic tubscontaining the margarine contained -( 5-310 ¡.g/kg (Startin & Gilbert, 1984).

1.3.6 Miscellaneous

The US Environmental Protection Agency (1990) estimated that 1,3-butadiene isemitted in automobile exhaust at 8.9-9.8 mg/mile (5.6-6.1 mg/km) and comprises about0.35% of total hydrocarbon in exhaust emissions. It has been detected in smoke generatedduring house fires at up to 15 ppm (33 mg/m3) (Berg et al., 1978).

Sidestream cigarette smoke contains 1,3-butadiene at approximately 0.4 mg/cigarette,and levels of 1,3-butadiene in smoky indoor environments are tyically 10-20 ¡.g/m3(Löfroth et al., 1989).

1.4 Regulations and guidelines

Occupational exposure limits and guidelines for 1,3-butadiene in sorne countries andregions are presented in Table II. Exposure limits were lowered in many countries in the late1980s.

1,3-Butadiene is regulated by the US Food and Drug Administration (1989) for use inresinous and polymeric coatings in can-end cements; for use only as a coating or coatingcomponent and limited to a level not to exceed 1% by weight of paper or paperboard incontact with foods; for use in semi-rigid and rigid acrylic and modified acrylic plastics inrepeat-use articles; for use in acrylonitrile-butadiene-styene copolymers used in closureswith sealing gaskets for food containers; and for use in textiles and textile fibres that come incontact with food.

2. Studies of Cancer in Humans

2.1 Cohort studies

The rubber industry, i.e., the manufacture of finished rubber goods, in which there ispotential exposure to 1,3-butadiene, amongother chemicals, has been evaluated previously;it was concluded that exposure in the rubber industry is carcinogenic to humans (IARC, 1982,1987b). The epidemiological studies that were evaluated did not, however, include specificinformation on styene-butadiene rubber manufacture, and it is these that are summarizedbelow. ln these descriptions, the histological descriptions of observed tumours given by theauthors are used, with ICD codes when available.

kajo

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1,3-BUTADIENE 251

Table 11. Occupational exposure Iimits and guidelines for l,3-butadiene

Country or region Year Concentration (mg/m3) Interpretationa

Australia 199 22 (carcinogen)Austria 1982 220 TWABelgium 199 22 (carcinogen) TWABrazil 1978 1720 TWAB ulgaria 1984 100 TWACzechoslovakia 199 20 TWA

40 STELDenmark 199 22 (carcinogen) TWAFinland 1987 73 (carcinogen) TWAGermany 1989 o (carcinogen in

animais; II AZ)Hungary 1990 10 (carcinogen) STELIndonesia 1978 2200 TWAItaly 1978 100 TWAMexico 1983 2200 TWANetherlands 1989 110 TWANorway 199 2.2 (carcinogen) TWAPoland 1984 100 TWARomania 1975 15() TWA2() CeilingSweden 199 20 (carcinogen) TWA

40 STEL (15-min)Switzerland 199 11 (carcinogen) TWAThiwan 1981 2200 TWAUnited Kingdom 1991 22 TWAUSA

ACGIH 1991 22 (suspected human TWAcarcinogen; AZ)

OS HA 1989 2200c TWAUSSR 1984 100 MACVenezuela 1978 2200 TWA

2750 CeilingYugoslavia 1971 500 TWA

From Cook (1987); US Occupational Safety and Health Administration (OSHA) (1989);Direktoratet for Arbeidstilsynet (199); Dutch Expert Committee for OccupationalStandards (199); American Conference of Governmental Industrial Hygienists(ACGIH) (1991); Health and Safety Executive (1991); International Labour Office(1991)ar A, 8-h time-weighted average; STEL, short-terr expsure limit; MAC, maximumallowable concentrationbSkin notation

'Te US OSHA has proposed to reduce the permissible expsure limits to 4.4 mg/m3for an 8-h TWA, 22 mg/m3 for a 15-min STEL and 2.2 mg/m3 for an 8-h TWA 'actionlevel; for a detailed discussion of this proposai, see US Occupational Safety and HealthAdministration (199).


Follow-up of mortality in a cohort of workers who manufactured 1,3-butadiene mono-mer in Texas (USA) (Downs et al., 1987) was extended through 1985 (Divine, 1990). Thecohort comprised men who had been employed for six months or more between the openingof the plant in 1943 and 31 December 1979. Vital status was ascertained through the SocialSecurity Administration or from state health departments. Of 2582 male employees, 1.9%were lost to follow-up and 32.0% were dead, 6% of these with no death certificate. Using USwhite men as the comparison population, the standardized mortality ratio (SMR) formortalityfrom aIl causes was 0.84 (826 deaths; 95% confidence interval (CI), 0.79-0.90) andthat for aIl cancers was 0.80 (163 deaths; 95% CI, 0.69-0.94). The only significantly elevatedSMR was for lymphosarcoma and reticulosarcoma (ICD8, 200) (2.29; 9 deaths; 95% ei,1.04-4.35), thus confirming the earlier report (Downs et al., 1987). Seven of the nine subjectshad first been employed before 1946. When analysis was carried out by years of employment,there was no trend in SMR with increasing length of employment for Iymphosarcoma orreticulosarcoma, and the only excess was seen for men with fewer than 10 years ofemployment. On the basis of the department listed on workers' personnel records, exposureto 1,3-butadiene was classified as low (not normally exposed to 1,3-butadiene), routine(exposed to 1,3-butadiene on a daily basis), non-routine (exposed intermittently to 1,3-butadiene, with possible exposure to peak concentrations higher than those with routineexposure) or unknown. Workers ever employed with routine exposure had a significantexcess of lympho- and reticulosarcoma (5 deaths; SMR, 5.61; 95% ei, 1.81-13.10); aIl fivedeaths were seen in workers who had been employed fewer than 10 years. The rates forcancers of the kidney and large intestine were nonsignificantly increased among men whohad worked for more than 10 years. Men who had had non-routine exposure had non-significantly increased risks for leukaemia (IeD8, 204-207) (SMR, 1.85; 6 deaths; 95% ei,0.68-4.03) and lymphosarcoma and reticulosarcoma (SMR, 1.26; 2 deaths; 95% CI, 0.14:'4.54).

Results were available from a study on the mortality of white male workers who hadbeen employed for at least six months in two US styene-butadiene rubber plants (Meinhardtet al., 1982). A total of 1662 workers employed in plant A between 1943 and 1976 and 1094workers employed in plant B between 1950 and 1976 were followed-up through 31 March1976. Nine deaths from cancer of the lymphatic and haematopoietic tissues (ICD7, 200-205)were seen in workers in plant A (SMR, 1.55 (95% CI, 0.71-2.95)); aIl these deaths occurredamong men who had first been employed between January 1943 and December 1945 (SMR,2.12; (95% CI, 0.97-4.02)), after which the process changed from batch to continuous feedoperation. No information was available, however, on the work histories of the subjects. TheSMR for leukaemia (ICD7, 204) in plant A among workers employed between 1943 and1945 was 2.78 (5 deaths (95% ei, 0.65-4.72)); two of the deaths had occurred within three

years of first employment. ln plant B, the numbers were very small: one death fromleukaemia was observed (0.99 expected), which occurred within four years of firstemployment; the SMR for lymphatic and haematopoietic neoplasms was 0.78 (2 deaths (95 %CI, 0.10-2.83)). Time-weighted average exposure to 1,3-butadiene was estimated after 1976to be about 10 times higher in plant B (mean, 13.5 ppm; SD, 29.9; range, 0.34-174) than inplant A (mean, 1.24 ppm; SD, 1.20; range, 0.11-4.17). Concomitant exposure to styene hadoccurred in plants A and B, andto traces of benzene at least in plant A.

1,3-BUTADIENE 253

Matanoski et aL. (1990a) investigated mortality patterns from 1943 (synthetic rubberproduction began in 1942) through 1982 of employees from eight styene-butadiene rubberplants in Canada and the USA, previously followed up through 1979 by Matanoski andSchwartz (1987). The study included aIl men who had been employed for at least one yearbetween 1943-or when their plant records were complete-and 1976. Canadian workerswere included in the more recent study only if they had worked 10 or more years or hadreached age 45 while stil employed, since this enabled more complete ascertainment of theirvital status through the company's insurance records. Of 12 113 employees, 2441 (20.2%)were deceased, 416 (3.4 % ) had unknown vi tal status and 9256 (76.4 % ) were stil living at theend of follow-up. Death certificates were obtained for 97.2 % of deceased individuals. On thebasis of US death rates for black and white men (since Ontario rates were similar to USrates), the SMRs for the entire cohort were as follows: 0.81 for aIl causes (2441 deaths; 95%CI, 0.78-0.85); 0.85 for aIl cancers (518 deaths; 95% ei, 0.78-0.93), 0.61 for lymphosarcoma(ICD8, 200) (seven deaths; 95% CI, 0.25-1.26), 1.20 for Hodgkin's disease (ICD8, 201)(eight deaths; 95% Ci, 0.52-2.37), 0.96 for leukaemia (ICD8, 204-207) (22 deaths; 95% ei,0.60-1.46) and 1.11 for 'other lymphatic' system cancers (ICD8, 202,203,208) (17 deaths;95% CI, 0.64-1.77). The SMR for lymphatic or haematopoietic cancers showed no cleartrend of increasing with increasing number of years worked or years since first exposure.When employees were classified according to the job held longest, production workers(presumed by the authors to be those with highest exposures to 1,3-butadiene) had an SMRfor deaths from aIl causes of 0.88 (594 deaths; 95% Ci, 0.81-0.95) and a significant excess ofother lymphatic cancer (SMR, 2.60; ni ne deaths; 95% ei, 1.19-4.94). When mortalityamongproduction workers was examined by race, the only significant excess was seen for leukaemiain blacks (three deaths; SMR, 6.56; 95% CI, 1.35-19.06). Of 92 deaths among blackproduction workers, six were due to ail lymphopoietic cancers (5.07; 1.87-11.07), and threeof these were leukaemias (6.56; 1.35-19.06). The rates for haematopoietic cancers amongmaintenance workers were lower than those of the production workers. Maintenance

workers showed increased risk for some digestive cancers, which were not evident inproduction workers. Workers in the two other job classification categories ('utility' and'other') showed no significant increase in SMR for any tye of cancer. A limitation of thisstudy, pointed out by the authors, was that missing information on 2391 employees meantthat they were excluded from the analysis of job department. Since many of these men wereactive in 1976 and are thus more likely to be alive than dead, the analysis by job is biasedtoward including more dead workers. The SMRs in this analysis may therefore be higher thanthose in the total cohort and are thus not directly comparable.

2.2 Case-ontrol studies

ln a case-control study nested within a cohort of 6678 US male rubber workers, deathsfrom cancers at the following sites were compared to those in a sample of the whole cohort:stomach (ieD8, 151) (41 deaths), colorectal (ICD8, 153-154) (63), respiratory tract (ICD8,160-163) (119), prostate (ICD8, 185) (52), urinary bladder (ICD8, 188) (13), lymphatic andhaematopoietic (ieD8, 200-209) (51) and lymphatic leukaemia (leD8, 204) (14)

(McMichael et al., 1976). A 6.2-fold increase in risk for lymphatic and haematopoieticcancers (99.9% ei, 4.1-12.5) and a 3.9-fold increase for lymphatic leukaemia (99.9% ei,


2.6-8.0) were found in association with more th an five years' work in manufacturing unitsproducing mainly styene-butadiene rubber during 1940-60. Of the five other cancer sitesinvestigated, only cancer of the stomach was associated with a significant (two-fold) increasein risk. (The Working Group noted that, although the confidence limits were calculated byamethod not used commonly, the results are significant at the 5% leveL.)

A case-control study nested within the US and eanadian cohort study described above(Matanoski et al., 1990a) involved 59 workers with lymphopoietic cancers, identified usingboth underlying and contributing causes listed on death certificates. Controls were 193workers without cancer, matched to the cases for plant, age, sex, date of hire, duration ofwork and survval up to date of death of the case (Santos-Burgoa, 1988; Matanoski et al.,1990b). Since the exposures to 1,3-butadiene and to styene were highly correlated, anattempt was made to discern to what extent each exposure contributed to the risk forleukaemia. Four industrial engineers who had no knowledge of the case or control status ofthe subjects estimated the intensity of exposure in each job, and duration of work wasdetermined from job histories. The sum of the product of intensity and duration for each jobresulted in a cumulative ranked exposure index for 1,3-butadiene and styene separately.When the log of the ranked exposure indexes was dichotomized above and below the meanscore for each exposure, 1,3-butadiene alone was associated with a risk for leukaemia (26deaths) of 7.61 (95% CI, 1.62-35.64), and styene alone gave a risk of 2.92 (95% ei,

0.83-10.27), each without adjustment for the other chemicaL. The relative risk for exposureto styene, adjusted for 1,3-butadiene, was 1.06 (95% CI, 0.23-4.96), while the risk for1,3-butadiene, adjusted for styene, was 7.39 (95% CI, 1.32-41.33). The same tye ofanalysisfor other lymphatic cancers (18 deaths), including non-Hodgkin's lymphoma (ICD8, 202)and multiple myeloma (ICD8, 203), gave a risk of 0.81 (95% ei, 0.28-2.38) for styeneadjusted for 1,3-butadiene and a risk of 1.68 (95% CI, 0.55-5.15) for 1,3-butadiene adjustedfor styene.

ln the population-based case-control study of cancers at multiple sites (excludingleukaemia) carried out in Montréal, Canada (Siemiatycki, 1991), described in detail on p. 95,4% of the entire study population had been exposed at sorne time to styene-butadienerubber. Elevated odds ratios were seen for cancer of the kidney: 2.0 (90% ei, 1.2-3.4) for 12cases with 'any' exposure and 2.9 (1.0-8.3) for three cases with 'substantial exposure. For

non-Hodgkin's lymphoma, the odds ratios were 0.9 (0.5-1.7) for seven cases with 'any'exposure and 1.5 (0.4-5.1) for two cases with 'substantial exposure.

3. Studies of Cancer in Experimental AnimaIs

3.1 Inhalation

3.1.1 Mouse

Groups of 50 male and 50 female B6e3Fi mice, eight to nine weeks of age, were exposedto 625 or 1250 ppm (1380 or 2760 mg/m3) 1,3-butadiene (minimum purity, ~ 98.9%) for 6 hper dayon five days per week for 60 weeks (males) or 61 weeks (females). An equal numberof animaIs sham-exposed in chambers served as controls. The study was terminated after 61weeks because of a high incidence of lethal neoplasms in the exposed animaIs. The numbers

1,3-BUTADIENE 255

of survvors were: males-49/50 control s, 11/50 low-dose and 7/50 high-dose; females-46/50 controls, 14/50 low-dose and 30/50 high-dose. Haemangiosarcomas originating inthe heart with metastases to various organs were found in: males-0/50 controls, 16/49(p .c 0.001) low-dose and 7/49 (p = 0.006) high-dose-and females-0/50 controls, 11/48(p .c 0.001) low-dose and 18/49 (p .c 0.001) high-dose (Fisher exact test). (The WorkingGroup noted that the incidence of haemangiosarcomas of the heart in historIcal contraIs was1/2372 in males and 1/2443 in femaIes.) Other tyes of neoplasm for which the incidences

were increased (Fisher exact test) in animaIs of each sex were malignant lymphomas:males-0/50 controls, 23/50 (p .c 0.001) low-dose and 29/50 (p .c 0.001) high-dose;

females-1/50 controls, 10/49 (p = 0.003) low-dose and 10/49 (p = 0.003) high-dose;

alveolar bronchiolar adenomas or carcinomas of the lung: males-2/50 contraIs, 14/49(p .c 0.001) low-dose and 15/49 (p .c 0.001) high-dose; females-3/49 control s, 12/48(p = 0.01) low-dose and 23/49 (p .c 0.001) high-dose; papillomas or carcinomas of theforestomach: males-0/49 controls, 7/40 (p = 0.003) low-dose and 1/44 (p = 0.473) high-dose; females-0/49 controls, 5/42 (p = 0.018) low-dose and 10/49 (p .c 0.001) high-dose.Tumours that occurred with statistIcaIly significantly increased incidence in females onlyincluded hepatocellular adenoma or carcinoma of the liver: 0/50 controls, 2/47 (p = 0.232)low-dose and 5/49 (p = 0.027) high-dose; acinar-cell carcinoma of the mammary gland: 0/50controls, 2/49 low-dose and 6/49 (p = 0.012) high-dose; and granulosa-cell tumours of theovary: 0/49 controls, 6/45 (p = 0.01) low-dose and 12/48 (p .c 0.001) high-dose (US NationalToxicology Program, 1984; Huff et al., 1985).

Groups of 60 male B6C3Fi and 60 male NIH Swiss mice, four to six weeks of age, wereexposed to 0 or 1250 ppm (2760 mg/m3) 1,3-butadiene (? 99.5% pure) for 6 h perdayon fivedays per week for 52 weeks. A group of 50 male B6e3Fi mice was exposed similarly to1,3-butadiene for 12 weeks and held until termination of the experiment at 52 weeks. Theincidence ofthymic lymphomas was 1/60 control B6e3Fi mice, 10/48 B6C3Fi mIce exposedfor 12 weeks, 34/60 B6C3Fi mIce exposed for 52 weeks and 8/57 NIH Swiss mice exposed for52 weeks. Haemangiosarcomas of the heart were observed in 5/60 B6C3Fi mIce and 1/57NIH Swiss mice (Irons et al., 1989). (The Working Group noted the absence of reporting onNIH Swiss control mice.)

ln studies designed to characterize exposure-response relationships further, groups of70-90 male and 70-90 female B6C3Fi mice, 6.5 weeks of age, were exposed to 0, 6.25, 20,62.5,200 or 625 ppm (0.14, 44, 138,440 or 1380 mg/m3) 1,3-butadiene (purity, ? 99%) for6 h per day on five days per week for up to two years. Ten animaIs per group were kiled andevaluated after 40 and 65 weeks of exposure. Survval was significantly reduced (p .c 0.05) inaIl groups of mice exposed to 1,3-butadiene at 20 ppm or higher; terminal survvors were:males, 35/70 controls, 39/70 at 6.25 ppm, 24/70 at 20 ppm, 22/70 at 62.5 ppm, 3/70 at 200ppm and 0/90 at 625 ppm; females, 37/70 controls, 33/70 at 6.25 ppm, 24/70 at 20 ppm; 11/70at 62.5 ppm; 0/70 at 200 ppm and 0/90 at 625 ppm. Tumours for which the rates weresignificantly increased by exposure to 1,3-butadiene are shown in Table 12 (Melnick et al.,1990).

Groups of 50 male B6C3Fi mice, 6.5 weeks of age, were exposed to 1,3-butadiene(purity, ? 99%) for 6 h per day on five days per week at 200 ppm (442 mg/m3) for 40 weeks,625 ppm (1380 mg/m3) for 13 weeks, 312 ppm (690 mg/m3) for 52 weeks or 625 ppm

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1,3-BUTADIENE 257

(1380 mg/m3) for 26 weeks. After the exposures were terminated, the animaIs were placed incontrol chambers for up to 104 weeks. A group of 70 males served as chamber controls (0ppm). Survval was reduced in aIl treated groups; the numbers of survvors at the end of thestudy were 35 controls, nine exposed to 200 ppm, five exposed to 625 ppm for 13 weeks, oneexposed to 312 ppm and none exposed to 625 ppm for 26 weeks. Tumours for which the rateswere significantly increased by exposure to 1,3-butadiene are shown in Thble 13 (Melnick etal., 1990).

3.1.2 Rat

Groups of 100 male and 100 female Sprague-Dawley rats, five weeks of age, wereexposed to 0, 1000 or 8000 ppm (2200 or 17 600 mg/m3) 1,3-butadiene (minimal purity,99.2%) for 6 h per day on five days per week for 111 weeks (males) or 105 weeks (females).Survval was reduced in low- and high-dose females and in high-dose males; the numbers ofsurvvors were: males-45 control, 50 low-dose and 32 high-dose; females-46 control, 32low-dose and 24 high-dose. Tumours that occurred at significantly increased incidence inmales were exocrine adenomas and carcinomas of the pancreas (3 control, 1 low-dose, Il(p .: 0.05) high-dose) and Leydig-cell tumours of the testis (0 control, 3 low-dose, 8

(p .: 0.01) high-dose). Those that occurred at significantly increased incidence (Fisher exacttest) in females were follicular-cell adenomas and carcinomas of the thyroid gland (0 control,410w-dose, 11 (p .: 0.001) high-dose) and benign and malignant mammary gland tumours(50 control, 79 low-dose and 81 high-dose, with a significant, dose-related trend (p .: 0.001);most of the latter were fibroadenomas: 40 control, 75 (p .: 0.001) low-dose, 67 (p .: 0.01)high-dose. Tumours that occurred onlywith positive trends (Cochran-Armitage trend test) infemales were sarcomas of the uterus (p .: 0.05; 1 control, 4 low-dose, 5 high-dose) andcarcinomas of the Zymbal gland (p .: 0.01; 0 control, 0 low-dose, 4 high-dose ) (Owen et al.,1987; US Occupational Safety and Health Administration, 1990). (The Working Groupnoted that differences in tumour incidence between groups were not analysed usingstatistical methods that took into account differences in mortality between control andtreated groups.)

3.2 Carcinogenicity of metabolites

Mouse: D,L-l,2:3,4-Diepoxybutane (IARC, 1976), an intermediate of 1,3-butadienemetabolism, induced 10/30 papilomas and 6/30 squamous-cell carcinomas of the skin whenapplied at 3 mg three times per week for life to the skin of female Swiss mice (Van Duuren etaL., 1965). 1,2-Epoxy-3-butene (vinyloxirane), another intermediate in 1,3-butadiene meta-bolism, induced 4/30 skin tumours when applied at 100 mg three times per week to the skin ofmale Swiss mice (Van Duuren et al., 1963). Subcutaneous injection of D,L-1,2:3,4-diepoxy-butane at 0.1 and 1.1 mg/animal in tricapiylin once per week for one year induced localfibrosarcomas in 5/50 and 5/30 female Swiss mice; no tumour was observed in three solvent-treated control groups. Administration of D,L-l,2:3,4-diepoxybutane at 1 mg/animal intricapiylin once per week for one year induced local fibrosarcomas in 9/50 Sprague-Dawley rats, compared with none in controls (Van Duuren et al., 1966).

~00

Table 13. Thmour incidences (1) and percentage mortality-adjusted tumour rates (R) in male mIce exposed

to l,3-butadiene in stop-exposure studies (After exposures were terminated, animais were placed in controlchambers until the end of the study at 104 weeks.)

Tumour Exposure ..~

0 200 ppm, 40 wk 625 ppm, 13 wk 312 ppm, 52 wk 625 ppm, 26 wk:;()

1 R 1 R 1 R 1 R 1 R ~0Z

Lymphoma 4170 8 12/50 35a 24/50 61a 15/50 55a 37/50 90a 0ci

Haemangiosarcoma of the 0170 0 15/50 47a 7/50 31a 33/50 87a 13/50 76a ~heart "'Alveolar-bronchiolar adenoma 22170 46 35/50 88a 27/50 87a 32/50 88a 18/50 89a ::

and carcinoma (J

dForestomach squamous-cell 1/70 2 6/50 20a 8/50 33a 13/50 52a 11/50 63apapiloma and carcinoma 5

Harderian gland adenoma and 6170 13 27/50 na 23/50 82a 28/50 86a 11/ 50 70a ~adenocrcinoma t'

VIPreputial gland carcinoma 0170 0 1/50 3 5/50 21a 4/50 21a 3/50 31a .tRenal tubular adenoma 0170 0 5/50 16a 1/50 5 3/50 15a 1/50 11

From Melnick et al. (199)aincreased compared with chamber con troIs (0 ppm), p .: 0.05, based on Iogistic regression analysis

kajo

Rectangle

1,3-BUTADIENE 259

3.3 Activated oncogenes

Tumours from the study of Melnick et aL. (1990) were evaluated in independent studiesfor the presence of oncogenes. Activated K-ras oncogenes were detected in 6/9 lung adeno-carcinomas, 3/12 hepatocellular carcinomas and 2/11 lymphomas obtained from B6e3FimIce exposed to 1,3-butadiene. A specific codon 13 mutation (guanine to cyosine trans-version) was found in most of the activated K-ras genes (Goodrow et al., 1990). ActivatedK-ras genes have not been found in spontaneously occurring liver tumours or Iymphomasfrom B6C3Fi mice (Reynolds et al., 1987; Goodrow et al., 1990) and were observed in only1/10 spontaneous lung tumours in this strain of mice (Goodrow et al., 1990).

4. Other Relevant Data

4.1 Absorption, distribution, metabolism and excretion

4.1.1 Humans1,3-Butadiene was reported to be metabolized to 1,2-epoxy-3-butene bya single human

postmitochondrial liver preparation; no metabolism was observed in a single lung sample(Schmidt & Loeser, 1985). (The Working Group was unable to determine whether the lungand the liver samples were from the same individual.) Incubations of 1,3-butadiene withhuman liver mIcrosomes from four subjects produced the chiral antipodes 1,2-epoxy-3-bute ne at ratios of 52-56% R- to 44-48% S-epoxybutene (Wistuba et al., 1989).

1,2-Epoxy-3-butene is further transformed by epoxide hydrolase and glutathione S-transferase, as measured by disappearance of the epoxide by human liver microsomes andcyosol (Kreuzer et al., 1991).

4.1.2 Experimental systems

Male Sprague-Dawley rats were exposed in closed inhalation chambers to various initialconcentrations of 1,3-butadiene to study the pharmacokinetic behaviour of the compound.Analysis of the resulting concentration decline curves of 1,3-butadiene in the gas phaserevealed that its metabolism was saturable. At less than 800-1000 ppm (1800-2200 mg/m3),1,3-butadiene was metabolized according to first-order kinetics; at higher exposure concen-trations (~ 1500 ppm (~ 3300 mg/m3), saturation range), a maximal metabolic rate of 220iimol/h per kg bw was observed; this was enhanced by pretreatment with Aroc1or 1254 (BoItet al., 1984). ln similar experiments in male B6C3Fi mice, saturation of 1,3-butadienemetabolism was observed at higher exposure concentrations (~ 2000 ppm (~ 4400 mg/m3Dat a maximal metabolIc rate of 400 iimol/h per kg bw. Pharmacokinetic analysis of the datasuggested that the species-related difference in the effect of 1,3-butadiene was due to morerapid uptake of the compound from the gas phase by mice (Kreilng et al., 1986a).

1,3- Butadiene is converted to 1,2-epoxy-3-butene by mixed-function oxidases in rat livermicrosomes in vitro. Pretreatment of rats with phenobarbital increases enzye activity(Malvoisin et al., 1979; BoIt et al., 1983). 1,2-Epoxy-3-butene is further metabolized to1,2:3,4-diepoxybutane and 3-butene-1,2-diol; the latter product is metabolized by mixed-function oxidases to 3,4-epoxy-1,2-butanediol (Malvoisin & Roberfoid, 1982) (Fig. 1).


Fig. 1. Possible pathways for metabolism of l,3-butadiene by rat liver microsomes

CH2= CH -CH = CH2

1 ,3-Butadiene

MFO

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'0/1,2-Epoxy-3-butene

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1

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lCH2-CH-CHOH -CH20H'0/3,4-Epoxy-1,2-butanediol

From Malvoisin and Roberfroid (1982); MFO, mixed-function oxidases; EH, epoxide hydrolase

Cytochrome P-450-mediated formation of 1,2-epoxy-3-butene from 1,3-butadiene alsooccurs in the presence of mouse liver microsomes, and crotonaldehyde has been shown to bea further metabolite (Elfarra et al., 1991).

1,2-Epoxy-3-butene is present in the expired air of rats and mice exposed to

1,3-butadiene (BoIt et al., 1983; Kreiling et al., 1987). When male Sprague- Dawley rats wereexposed in closed exposure chambers to concentrations of 1,3-butadiene higher than 2000ppm (4400 mg/m3), which result in the maximum possible metabolIc rate, about 4 ppm (8.8mg/m3) 1,2-epoxy-3-butene were measured in the gas phase under steady-state conditions.KInetic analysis revealed that only 29% of the predicted value of 1,3-butadiene metaboliteunder these conditions was avaIlable systemically as 1,2-epoxy-3-butene, which was consi-dered to be related to a first-pass metabolism of the 1,2-epoxy-3-butene originating in the

1,3-BUTADIENE 261

liver (Filser & BoIt, 1984). The exhalation of 1,2-epoxy-3-butene by two male Sprague-Dawley rats and six male B6C3Fi mice exposed in a closed system to 2000-4000 ppm(4400-8800 mg/m3)1,3-butadiene for 15 h was compared (Kreiling et al., 1987). After about2 h, rats had built up a constant concentration of 1,2-epoxy-3-butene at about 4 ppm(8 mg/m3), with no sign of toxicity. 1,2-Epoxy-3-butene concentrations in the experimentwith mice increased to about 10 ppm (22 mg/m3) after 10 h; and after 12 h, animaIs showedsigns of acute toxicity.

Studies on the disposition of inhaled (nose only) i4C-Iabelled 1,3-butadiene in Sprague-Dawley rats and B6C3Fi mice confirmed that mice metabolize 1,3-butadiene to a greaterextent than rats. Radiolabelled metabolites present in blood were separated according totheir volatility by vacuum line-cryogenic distilation (Dahl et aL., 1984). Blood samples takenfrom mice during exposure to 13 000 mg/m3 (7100 ppm) (sic) for 6 h contained two to fivetimes more radiolabelled 1,2-epoxy-3-butene than did the blood of rats (Bond et al., 1987).Three male cyomolgus monkeys (Ma ca ca fascicularis) were exposed by nose only to 10,310or 7760 ppm (22, 680 or 17 150 mg/m3)i4e-butadiene for 2 h. For exposures equivalent tothose in mice and rats, the concentrations of total 1,3-butadiene metabolites in blood were5-50 times lower in monkeys than in mice. The ranking of species was thus mice :; rats ?

monkeys (Dahl et al., 1991).Metabolic species differences were also investigated in vitro using liver preparations

from rats (Sprague-Dawley, Wistar), mice (NMRI and B6e3Fi), rhesus monkeys andhumans (Schmidt & Loeser, 1985). The ranking of species for 1 ,2-epoxy-3-butene formationwas: female mice :; male mice :; rats (humans) :; monkeys. (The Working Group notedthat the quantitative data on the human rate were derived from a single sample of liver.)

Repeated pretreatment of male Sprague-Dawley rats and male B6C3Fi ffice (inha-lation by nose only) with 1,3-butadiene at 13 600 mg/m3 (7600 ppm) for 6 h per day for fivedays had no effect on the ability of liver mIcrosomes isolated from these animaIs to meta-bolize 1,3-butadiene. The metabolism of 1,3-butadiene in vitro was depressed significantly,however, in microsomes from lungs of pre-exposed rats and mice compared to unexposedcontrols (Bond et al., 1988). Formation of 1,2-epoxy-3-butene was also observed after incu-bation of 1,3-butadiene with mouse and rat Iung tissue but not after incubation with lungtissue from monkeys or hum ans (Schmidt & Loeser, 1985). (The Working Group noted thatthe quantitative data on the human rate were derived from a single sample of lung.)

The inhalation pharmacokinetics of the metabolite 1,2-epoxy-3-butene were studied inmale Sprague-Dawley rats and male B6C3Fi mice in closed chambers. Whereas in rats noindication of saturation kinetIcs could be obtained up to exposure concentrations of 5000ppm (11 000 mg/m3), saturation occurred in mice exposed to 500 ppm (1100 mg/m3) or more

(Kreiling et al., 1987; Laib et aL., 1990).

4.2 Toxic effects

4.2.1 HumansThe toxic effects of combined exposures to 1,3-butadiene and other agents (e.g., styene,

chloroprene, hydrogen sulfide, acrylonitrile) have been reviewed (Parsons & Wilkins, 1976).Concentrations of several thousand parts per milion of 1,3-butadiene irritate the skin, eyes,nose and throat (Carpenter et aL., 1944; Wilson et al., 1948; Parsons & Wilkins, 1976).


Several studies have been reported on the effects of occupational exposure to1,3-butadiene, mainly from the ex-USSR and Bulgaria. Feware substantiated by detaIls onthe atmospheric concentration or duration of exposure, and control data are generally notprovided. The effects reported include haematological disorders (Batkina, 1966; Volkova &Bagdinov, 1969), kidney malfunction, larygotracheitis, irritation of the upper respiratoiy

tract, conjunctivitis, gastritis, various skin disorders, a variety of neuraesthenic symptoms(Parsons & Wilkins, 1976) and hypertension and neurological disorders (Spasovski et al.,1986).

Checkoway and Williams (1982) reported minimal changes in haematological indicesamong eight workers exposed to about 20 ppm (44.2 mg/m3) 1,3-butadiene, 14 ppm (59.5mg/m3) styene and 0.03 ppm (0.1 mg/m3) benzene, as compared to those among 145workers exposed to less than 2 ppm (4.4 mg/m3) 1,3-butadiene, 2 ppm (8.5 mg/m3) styeneand 0.1 ppm (0.3 mg/m3) benzene. Changes included a slight decrease in haemoglobin leveland a slight increase in red-cell mean corpuscular volume. (The Working Group consideredthat these changes cannot be interpreted as an effect of 1,3-butadiene on the bone marrow,particularly as alcohol intake was not evaluated.)


LCso values for 1,3-butadiene were reported to be 270 000 mg/m3 (122170 ppm) in miceexposed for 2 h and 285 000 mg/m3 (129 000 ppm) in rats exposed for 4 h; after 1 h ofexposure, rats were in a state of deep narcosis (Shugaev, 1969). Oral LDso values of 5.5 g/kgbw for rats and 3.2 g/kg bw for mice have been reported (US National Toxicology Program,1984).

ln female rats exposed to 1-30 mg/m3 (0.45-14 ppm) 1,3-butadiene for 81 days, morpho-logical changes were observed in liver, kidney, spleen, nasopharyx and heart (G.K. Rippreported in Crouch et al., 1979). ln groups of 24 rats exposed to 600-6700 ppm (1300-14 800 mg/m3) 1,3-butadiene for 7.5 h per day on six days per week for eight months, noadverse effect was noted, except for a slight retardation in growth with the highest concen-tration (Carpenter et al., 1944). Rats exposed to 2200-17 600 mg/m3 (1000-8000 ppm)1,3-butadiene for 6 h per day on five days per week for three months showed no treatment-related effect other than increased salivation in females (Crouch et al., 1979).

Groups of 110 male and 110 female CD Sprague-Dawley rats were exposed toatmospheres containing 0, 1000 or 8000 ppm (0,2200 or 17600 mg/m3) 1,3-butadiene for6 h per day on five days per week. The study was terminated when it was predicted thatsurvval would drop to 20-25% (105 weeks for females, 111 weeks for males). Ten animaIs ofeach sex from each group were kiled at 52 weeks. Treatment was assocIated with changes in

cIinical condition and lowering of body weight gain during the first 12 weeks, thennonsignificant changes, reduced survival and increases in certain organ weights and in theincidences of uncommon tumour tyes (for details, see p. 257). Increased mortality inhigh-dose males was accompanied by an increase in the severity of nephropathy (Owen et aL.,1987; Owen & Glaister, 1990).

B6e3Fi mice exposed to 0, 625 or 1250 ppm (1380 or 2760 mg/m3j 1,3-butadiene for

6 hper day on five days per week for 60-61 weeks had increased prevalerices of atrophy of theovary and testis, atrophy and metaplasia of the nasal epithelium, hyperplasia of the

1,3-BUTADIENE 263

respiratory and forestomach epithelium and liver necrosis (see also pp. 254-255) (USNational Toxicology Program, 1984).

Haematological changes in male B6C3Fi mIce exposed to 62.5, 200 or 625 ppm (138,440 or 1375 mg/m3) 1,3-butadiene for 6 h per day on five days per week for 40 weeks includeddecreased red blood cell count, haemoglobin concentration and packed red cell volume andincreased me an corpuscular volume. Similar changes occurred in female mice exposed to625 ppm (1375 mg/m3)1,3-butadiene (for details, see pp. 255-257) (Melnick et al., 1990).

The role of murine retroviruses on the induction of leukaemias and lymphomasfollowing inhalation of 1,3-butadiene was evaluated in a series of studies reviewed by Irons(1990). Exposure of groups of male B6C3Fi mice, which have the intact ecotropic murineleukaemia virus, to 1250 ppm (2750 mg/m3) 1,3-butadiene for 6 h per day on 6 days per weekfor 6-24 weeks resulted in a decrease in the number of circulating eryhrocyes, in totalhaemoglobin and in haematocrit and an increase in mean corpuscular volume. Leukopenia,due primarily to a decrease in the number of segmented neutrophils, and an increase in thenumber of circulating micronuclei were observed (Irons et al., 1986a). Persistent immu-nological defects were not detectable after this treatment (Thurmond et al., 1986). Exposureof male NIH Swiss mice, which do not possess intact endogenous ecotropic murineleukaemia virus, produced similar results (Irons et al., 1986b).

A further study was conducted to examine the expression and behaviour of endogenousretroviruses in these strains during the preleukaemic phase of 1,3-butadiene exposure.Chronicexposure ofB6C3Fi mice to 1,3-butadiene (1250 ppm (2740 mg/m3)) for 6 h per dayon five days per week for 3-21 weeks increased markedly the quantity of ecotropic retrovirusrecoverable from the bone marrow, thymus and spleen. Expression of other endogenousretroviruses (xenotropic, MCF-ERV) was not enhanced. No virus of any tye was found insimilarly treated NIH Swiss mice (Irons et al., 1987a).

Enhanced susceptibility to 1,3-butadiene-induced leukaemogenesis as a result of theability to express the retrovirus was suggested by the finding that exposure to 1250 ppm1,3-butadiene for one year resulted in a 57% incidence of thymIc lymphoma in B6C3F 1 mice

(with expression of the virus) and a 14% incidence in NIH Swiss (without viral expression)(Irons et aL., 1989).

4.3 Reproductive and developmental etTects

4.3.1 HumansNo data were avaIlable to the Working Group.


Fertility was reported to be unimpaired in mating studies in rats, guinea-pigs and rabbitsexposed to 600, 2300 or 6700 ppm (1300,5000 or 14 800 mg/m3) 1 ,3-butadiene by inhalationfor 7.5 h per day on six days per week for eight months (Carpenter et al., 1944). (The WorkingGroup noted the incomplete reporting of this study).

Pregnant Sprague-Dawley rats (24-28 per group) and Swiss (CD-l) mice (18-22 pergroup) were exposed to atmospheric concentrations of 0, 40, 200 or 1000 ppm (0, 88, 440 or2200 mg/m3) 1,3-butadiene for 6 h per day on days 6-15 of gestation and kiled on gestationday 18 (mice) or 20 (rats). Subsequently, the uterine contents were evaluated; individual fetal


body weights were recorded; and external, visceral and skeletal examinations wereperformed. ln rats, maternaI toxicity was observed in the 1000-ppm group in the form ofreduced extragestational weight gain and, during the first week of treatment, decreased bodyweight gain. Under these conditions, there was no evidence of developmental toxicity.MaternaI toxicity was observed in mice given 200 and 1000 ppm 1,3-butadiene; 40 ppm andhigher concentrations of 1,3-butadiene caused significant exposure-related reductions in themean body weights of male fetuses. Mean body weights of female fetuses were reduced at the200 and 1000 ppm exposure levels. No increased incidence of malformations was observed ineither species. The frequency of fetal variations (supernumerary ribs, reduced sternebralossification) was significantly increased in mice exposed to 200 and 1000 ppm. ln a study ofsperm-head morphology, groups of 20 male B6C3Fi mice were exposed to atmosphericconcentrations of 0, 200, 1000 or 5000 ppm (0, 440,2200 or Il 000 mg/m3J 1,3-butadiene for6 h per day for five consecutive days. Small, concentration-related increases in the frequencyof abnormal sperm morphology were seen five weeks after exposure (the only time ofexamination) (Hackett et aL., 1987; Morrissey et al., 1990). (The Working Group noted thatsequential examinations were not conducted after exposure to de

termine the effect of1,3-butadiene on aIl stages of gamete development. J

4.4 Genetic and related effects

4.4.1 Humansln an abstract of a study of workers engaged in the manufacture of 1,3-butadiene in

Finland, cyogenetic analysis revealed no increase in the frequency of sister chromatidexchange, chromosomal aberrations or micronucleus formation in peripheral blood. Theambient air concentrations of 1,3-butadiene were generally -c 1 ppm ( -c 2.2 mg/m3J, and the

workers used protective clothing and respirators (Sorsa et al., 1991).

4.4.2 Experimental systems (see also Tables 14-16 and Appendices 1 and 2)

The genetic toxicology of 1,3-butadiene has been reviewed (Rosenthal, 1985; deMeester, 1988; Brown, 1990). Additional information on 1,3-butadiene is included in areview by the Dutch Expert Committee for Occupational Standards (1990). The genetic andrelated effects of two main metabolites of 1,3-butadiene (1,2-epoxy-3-butene and 1,2:3,4-diepoxybutane) were reviewed by Ehrenberg and Hussain (1981) and de Meester (1988).

(a) 1,3-Butadiene

1,3-Butadiene was mutagenic to Salmonella typhimurium TA1530 in the presence ofliver S9 from phenobarbital- or Aroclor 1254-pretreated rats but was not mutagenic in thepresence of uninduced rat liverS9 (de Meester et al., 1980). It was also mutagenic to TA1535in the presence of Arcolor 1254-induced rat S9, uninduced rat S9 and uninduced mouse S9but was not mutagenic in the presence of uninduced human S9 (Arce et aL., 1990).

1,3-Butadiene gave negative results in tests for somatic mutation and recombination inDrosophila melanogaster.

1,3-Butadiene was not active in the L5178Y mouse lymphoma forward mutation assay.A weak positive response was reported for sister chromatid exchange induction in Chinesehamster ovary (CHO) cells.

i,3-BUTADIENE 265

ln one study, sister chromatid exchange was induced weakly in hum an whole bloodlymphocye cultures after treatment with 1,3-butadiene in the presence and absence ofAroclor-1254-induced rat liver S9. No sister chromatid exchange was induced in anotherstudy in which S9 from a variety of sources was used, including mouse and human.

When B6C3F1 mIce and Wistar rats were exposed to 14C-1,3-butadiene in a closedexposure system, radiolabel was associated with hepatic nucleoproteins and DNA from bothspecies. The association of radiolabel with nucleoproteins was about two times stronger inmIce th an in rats, but the association with DNA was similar in the two species (Kreiling et al.,1986b). Acid hydrolysis of DNA isolated from the livers of mice exposed to 14C-1,3-

butadiene revealed the presence of two identifiable alkylation products: 7-N-(I-hydroxy-3-buten-2-yI)guanine and 7-N-(2,3,4-trihydroxybutyl)guanine. These were not found insimilarly exposed rats (Jelitto et al., 1989).

After a 7-h exposure of mice and rats to 1,3-butadiene at 250, 500 or 1000 ppm (550,1100 or 2200 mg/mg3), alkaline elution profiles from the livers and lungs showed theoccurrence of protein-DNA and DNA-DNA cross-links with aIl doses of 1,3-butadiene inmice but not in rats. This finding was interpreted as a biological effect in mice of thebifunctional alkylating metabolite, 1,2:3,4-diepoxybutane (Jelitto et aL., 1989). ln anotherstudy, there was no evidence of the formation of cross-links in DNA isolated from the liversof 1,3-butadiene-treated mice or rats (Ristau et al., 1990).

No unscheduled DNA synthesis was evident in the livers of either Sprague-Dawley ratsor B6C3F1 mIce after exposure to 10 000 ppm (22 000 mg/m3) 1,3-butadiene.

1,3-Butadiene increased the frequency of sister chromatid exchange in bone-marrowcells of mice, but not of rats, exposed in vivo. Chromosomal aberrations and micronuclei, butnot aneuploidy, were induced in mice by 1,3-butadiene, but, in a single study, micronucleiwere not induced in rats.

ln a study of dominant lethal mutations, male Swiss CD-1 mice were exposed to 0, 70,200, 1000 or 5000 ppm (155, 440,2200 or 11050 mg/m3) 1,3-butadiene for 6 h per dayfor fivedays and then mated weekly for eight weeks. After one week, a significant increase wasobserved in the number of de ad implants in females mated with males exposed to 1000 ppm(smaller increases were seen at 200 and 5000 ppm). Two weeks after exposure, the proportionof de ad implants was increased in the 200- and 1000-ppm groups (details not given).Sperm-head abnormalities were induced in exposed males (Morrissey et aL., 1990).

(b) 1,2-Epoxy-3-butene

1,2-Epoxy-3-butene reacts with DNA to give two main alkylated products, 7-(2-hydroxy-3-buten-1-yl)guanine and 7-(1-hydroxy-3-buten-2-yl)guanine (eitti et aL., 1984).

1,2-Epoxy-3-butene was mutagenic to bacteria in the absence of an exogenous

metabolIc system. It did not induce unscheduled DNAsythesis in rat or mouse hepatocyesbut induced sister chromatid exchange in eHO cells and in cultured human lymphocyes. ln asingle study, it induced sister chromatid exchange and chromosomal aberrations in mousebone marrow in vivo.

(c) 1,2:3,4-Diepoxybutane

1,2:3,4-Diepoxybutane induced interstrand cross-links in DNA by reaction at the N7position of guanine (Lawley & Brookes, 1967).

Table 14. Genetic and related effects of l,3-butadiene ~0\Test system Resulta Doseb Reference

LED/HID

Without Withexogenous exogenousmetabolic metabolicsystem system

SAO, Salmonella tyhimun'um TA100, revers mutation - - 1300.~~ Arce et al. (199)SA3, Salmonella typhimun'um TA1530, reverse mutation - + 86. ~~ de Meester et al. (1980)SAS, Salmonella typhimun'um TA1535, revers mutation - (+ ) 650. ~~ Arce et al. (199) -SA9, Salmonella tyhimun'um TA98, revers mutation - - 1300. ~~ Arce et al. (199) ~SAS, Salmonella typhimun'um TA97, revers mutation - - 1300.~~ Arce et al. (199) ~DMM, Drosophila melanogaster, wing spot mutation - 0 1~~.~~ Victorin et al. (199) ~05T, Oene mutation, mous Iymphoma L5178Y cells, tk locs - - 650.~~ McGregor et al. (1991) 0sic, Sister chromatid exchange, Chinese hamster ovary cells in vitro - (+ ) 1.3500 Sasiadek et al. (1991a) ZSHi, Sister chromatid exchange, human lymphoces in vitro - - 2160.~~ Arce et al. (199) 0

0SHi, Sister chromatid exchange, human lymphoces in vitro + + 108.~~ Sasiadek et al. (1991b)

~DVA DNA-DNA cros-links Sprague-Dawley rats in vivo - 0 310.~~ inhal. 8 h/d, 7 d Ristau et al. (199)"'DV A DNA-DNA cros-links B63F1 mice in vivo - 0 3100.~~ inhal. 8 h/d, 7 d Ristau et al. (1990) 0:BVD, DNA alkylation, male Wistar rat liver cells in vivo - 0 550.~~ Jelitto et al. (1989) r:

BVD, DNA alkylation, male B63F1 mouse liver cells in vivo + 0 680. ~~ Jelitto et al. (1989) ~0DVA DNA-DNA cros-links Sprague-Dawley rat liver/lung in vivo - 0 550.~~ Jelitto et al. (1989)

5DVA DNA-DNA cros-links B63F1 mouse liver/lung in vivo + 0 680. ~~ Jelitto et al. (1989)UPR, Unsheduled DNA synthesis, Sprague-Dawley rats in vivo - 0 40.~~ inhal. C Arce et al. (199) ~tTUPR, Unscheduled DNA synthesis, Sprague-Dawley rats in vivo - 0 40.~~ inhal. d Arce et al. (1990) VlUVM, Unscheduled DNA synthesis, B63F1 mice in vivo - 0 1160.~~ inhal. C Arce et al. (199) ~

UVM, Unscheduled DNA synthesis, B63F1 mice in vivo - 0 11600.~~ inhal. d Arce et al. (1990)SV A Sister chromatid exchange, male B6C3F1 mouse bone marrow in vivo + 0 116.~~ inhal. 6 h/de Cunningham et al.

(1986)SVA Sister chromatid exchange, male Sprague-Dawley rat bone marrow - 0 4000.~~ inhal. 6 h/de Cunningham et al.in vivo(1986)SVA Sister chromatid exchange, male B63F1 mouse bone marrow in vivo + 0 7.~~ inhal. 6 h/d, 10 d Tice et al. (1987)

MVM, Micronucleus test, male B63F1 mouse bone marrow in vivo + 0 116.~~ 6 hW Cunningham et al.(1986)MVM, Micronucleus test, male B63F1 mouse peripheral bloo in vivo + 0 70.~~ inhal. 6 h/d, 10 d Tice et al. (1987)

MVM, Micronucleus test, male B63F1 mouse peripheral bloo in vivo + 0 7. () Jauhar et al. (1988)MVM, Micronucleus test, NMRI mouse bone marrow in vivo + 0 35.~~ inhal. 23 h Victorin et al. (1990)

Table 14 ( contd)

Test system Resulta Doseb ReferenceLED/HID


MVR, Micronucleus test, male Sprague-Dawley rat bone marrow in vivo - 0 40. ~~. Cunningham et al.(1986) ..

CBA Chromosomal aberrations, male B63F1 mouse bone marrow in vivo + 0 1500.0000g inhal. 6 hg Irons et al. (1987b) \.1

CBA Chromosomal aberrations, male NIH Swiss mouse bone marrow + 0 1500.00g inhal. 6 hg Irons et al. (1987b) t:in vivo C

CBA, Chromosmal aberrations, male B6C3F1 mouse bone-marrow in vivo + 0 700.~~ Tice et al. (1987) ~· Aneuploidy, male NIH Swiss mouse bone marrow in vivo - 0 1500.~~ inhal. 6 hg Irons et al. (1987b) U-· Aneuploidy, male B63F1 mouse bone marrow in vivo - 0 1500.~~ inhal. 6 hg Irons et al. (1987b) t'DLM, Dominant lethal test, Swiss CD-1 mouse + 0 233.0000 Morrssey et al. (199) Z

t'SPM, Spenn abnonnality test, mouse + 0 1165.0000 Morrssey et al. (1990)

a+, poitive; (+), weakly poitive; -, negative; 0, not tested; ?, inconclusive (variable response in several experiments within an adequate study)

ÕJn-vitro tests, ¡.g/ml; in-vivo tests, mg!g bwc6 h treatment on day 1, 3 h on day 2, liver sampled 2 h laterd6 h treatment on days 1 and 2, liver sampled 18 h later

'For two days, killed 24 h after the second exposurelfive days/week for 13 weeksBKlled at 24, 48, 72 and 96 h after cessation of expsure.Data not displayed on profiles

~..

~CI

Table 15. Genetic and related etTects of 1,2-epoxy-3-butene

Test systemResulta Doseb Reference

LED/HID

Without Withexogenous exogenousmetabolic metabolic ..system system ;:

:;('SAO, Salmonella typhimurium TAl00, reverse mutation

+ 0 350.~~ de Meester et al. (1978) ~SAO, Salmonella typhimurium TAl00, reverse mutation+ 0 26. ~~ Gervasi et al. (1985) 0SA3, Salmonella typhimurium TA1530, revers mutation+ 0 175.~~ de Meester et al. (1978) ZSAS, Salmonella typhimurium TA1535, reverse mutation+ 0 1750.~~ de Meester et al. (1978) 0aSA7, Salmonella typhimurium TA1537, reverse mutation - 0 8750.~~ de Meester et al. (1978)

~SA8, Salmonella typhimurium TA1538, reverse mutation - 0 8750.~~ de Meester et al. (1978)

"'SA9, Salmonella typhimurium TA98, reverse mutation - 0 8750.~~ de Meester et al. (1978) :iSA9, Salmonella typhimurium TA98, reverse mutation - 0 105.~~ Gervasi et al. (1985) C/EC\v Escherichia coli WP uvrA revers mutation

+ 0 O. ~~ Hemminki et al. (1980) ~0KPF, Klebsiella pneumoniae, fluctuation test

+ 0 70. ~~ Voogd et al. (1981) t"VRp, Vnscheduled DNA synthesis, rat hepatoctes in vitro - 0 100. ~~ Arce et al. (1990) CUIA Unscheduled DNA synthesis, mouse hepatoctes in vitro - 0 100.~~ Arce et al. (1990) ~tisic, Sis ter chromatid exchange, Chinese hamster ovary cells in vitro

+ + 0.0700 Sasiadek et al. (1991a)VI

SHI. Sis ter chromatid exchange, human lymphocytes in vitro+ 0 1.7500 Sasiadek et al. (1991b) ..SVA Sister chromatid exchange, male C57BI/6 mouse bone marrow in vivo+ 0 25. ~~ Sharief et al. (1986)CBA Chromosomal aberrations, male C57BI/6 mouse bone marrow in vivo+ 0 25. ~~ Sharief et al. (1986)

a+, poitive; (+ ~ weakly poitive; -, negative; 0, not tested; ?, inconclusive (variable response in several expriments within an adequate study)

b¡n-vitro tests, ¡.g/ml; in-vivo tests, mglg bw

Table 16. Genetic and related effects of 1,2:3,4-diepoxybutane

Test system Resulta Doseb ReferenceLED/HID


PRB, Prophage induction, Badllus megaterium + 0 O. ~~ Lwoff (1953)

PRB, Prophage induction, Pseudomonas pyocyanea + 0 O. ~~ Lwoff (1953)

PRB, Prophage induction, Escherichia coli K-12 + 0 7.500 Heinemann & Howard

(1964)ECB, Escherichia coli H54û, DNA repair induction + 0 2500.~~ Thielmann & Gersbach

(1978)SAO, Salmonella typhimurium TAloo, reverse mutation (+ ) (+ ) 50.~~ Dunkel et al. (1984) ..SAO, Salmonella typhimurium TAloo, reverse mutation + 0 20. ~~ Gervasi et al. (1985) t.SAS, Salmonella typhimurium TA1535, reverse mutation 0 25. ~~ McCann et al. (1975)

1

+ t.SAS, Salmonella typhimurium TA1535, reverse mutation + + 5. ~~ Rosenkranz & Poirier C

(1979)~SAS, Salmonella typhimurium TA1535, reverse mutation + + 5. ~~ Dunkel et al. (1984)

SA7, Salmonella typhimurium TA1537, revers mutation 167.~~ Dunkel et al. (1984)..- - ti

SA8, Salmonella typhimurium TA1538, reverse mutation - - 50.~~ Rosenkranz & Poirierêi

(1979)SA8, Salmonella typhimurium TA1538, reverse mutation - - 167.~~ Dunkel et al. (1984)SA9, Salmonella typhimurium TA98, reverse mutation - - 167.~~ Dunkel et al. (1984)SA9, Salmonella typhimurium TA98, reverse mutation - 0 60.~~ Gervasi et al. (1985)

EC\Y Escherichia coli WP2 uvrA reverse mutation (+ ) (+ ) 167.~~ Dunkel et al. (1984)ECR, Escherichia coli B, reverse mutation + 0 1720. ~~ Glover (1956)

ECR, Escherichia coli B/r, revers mutation + 0 860.~~ Glover (1956)

KPF, Klebsiella pneumoniae, fluctuation test + 0 4. ~~ Voogd et al. (1981)

* Saccharmyces cereisiae D7, gene conversion + + 130. ~~ Sandhu et al. (1984)

SCH, Saccharmyces cereisiae D4, mitotic gene conversion + 0 430.~~ Zimmennann (1971)

SCH, Saccharmyces cereisiae D81, mitotic crossing-over + 0 20.~~ Zimmennann & Vig(1975)

SCH, Saccharmyces cereisiae D3, mitotic recombination + + 40. ~~ Sim mon (1979)

* Saccharmyces cereisiae D7, mitotic crossing-over + + 130.~~ Sandhu et al. (1984)

* Saccharmyces cereisiae, reverse mutation + 0 40. ~~ Polakowska &Putrament (1979)

~I.

NTable 16 (contd)

25Test system

Resulta Doseb Reference

LED/HID


SCF, Saccharmyces cereisiae, cyoplasmic petite mutation- 0 40.~~ Polakowska &

Putrament (1979)*Saccharmyces cereisiae, mitochondrial mutation+ 0 40.~~ Polakowska & ..

;:Putrament (1979) ~*Saccharmyces cereisiae D7, reverse mutation

+ + 130. ~~ Sandhu et al. (1984) ()NCR, Neurospra crasa, reverse mutation+ 0 4300. ~~ Kölmark & ~Westergaard (1953) 0NCR, Neurospora cra sa, reverse mutation+ 0 1720. ~~ Pope et al. (1984) ZDMM, Drosophila melanogaster, recombination and mutation, spot test+ 0 100.~~ Graf et al. (1983) 00

DMX, Drosophi1a melanogaster, sex-Iinked recessive lethaI mutation+ 0 100.~~ Bird & Fahmy (1953)

5:DMX, Drosophila melanogaster, sex-linked recessive lethal mutation

+ 0 175.~~ Sankaranarayanan et al.'"(1983) ::

DMX, Drosophila melanogaster, sex-linked recessive lethal mutation+ 0 100.~~ Fahmy & Fahmy (1970) U'DMC, Drosophila melanogaster, chromosomal deletion+ 0 100. ~~ Fahmy & Fahmy (1970) ~DIA DNA-DNA cross-links, B6C3F1 mouse liver DNA in vitro+ 0 4. ~~ Ristau et al. (1990) 0

t'G5T, Gene mutation, mouse Iymphoma L5178Y cells, tk locs

+ 0 0.300 McGregor et al. (1988) Csic, Sister chromatid exchange, Chinese hamster CHG cells in vitro+ 0 0.0250 Perr & Evans (1975) ~sic, Sister chromatid exchange, Chinese hamster CHG cells in vitro+ + 0.0100 Sasiadek et al. (1991a) tT

VISHI. Sis ter chromatid exchange, human lymphocytes in vitro

+ 0 O. 1250 Wiencke et al. (1982) ~SHI. Sister chromatid exchange, human lymphoctesC in vitro- 0 0.0100 Porfirio et al. (1983)SHI. Sister chromatid exchange, human lymphoctes in vitro+ 0 0.0100 Porfirio et al. (1983)SHI. Sister chromatid exchange, human lymphocytes in vitro+ + 0.04 Sasiadek et al. (1991b)CHF, Chromosomal aberrations, human skin fibroblastsd in vitro+ 0 0.0100 Auerbach & Wolman

(1978)CHF, Chromosomal aberrations, human skin fibroblasts in vitro- 0 0.0100 Auerbach & Wolman

(1978)CHI. Chromosomal aberrations, human Iymphoblastoid cell Iinese+ 0 0.0100 Cohen et al. (1982)CHI. Chromosomal aberrations, human Iymphoctesa in vitro+ 0 0.100 Marx et al. (1983)CHI. Chromosomal aberrations, human lymphoctes in vitro(+ ) 0 O. 100 Marx et al. (1983)CHI. Chromosomal aberrations, human lymphocytes in vitro - 0 0.0100 Porfirio et al. (1983)CHI. Chromosomal aberrations, human lymphocytesC in vitro+ 0 0.0100 Porfirio et al. (1983)

Table 16 (contd)

Test system

CIH, Chromosomal aberrations hum an bone-marrow cellse in vitroCIH, Chromosmal aberrtions, nonnal human bone-marrow cells in vitroHMM, Host-mediated asay, mutation, S. typhimurium TA1530 in miceHMM, Host-mediated asay, mitotic recombination, S. cereisiae D3 in miceSVA Sister chromatid exchange, mouse bone-marrow cens in vivoSVA Sister chromatid exchange, mouse alveolar macrophages in vivoSVA Sister chromatid exchange, mouse regenerating liver cells in vivoSVA Sister chromatid exchange, NMRI mouse bone-marrow cells in vivoSVA Sister chromatid exchange, NMRI mouse bone-marrow cells in vivoSVA Sister chromatid exchange, Chinese hamster bone-marrow cens in vivoSVA Sister chromatid exchange, Chinese hamster bone-marrow cells in vivoCBA Chromosomal aberrations, NMRI mouse bone marrow in vivoCBA Chromosomal aberrations, NMRI mouse bone marrow in vivoCBA Chromosmal aberrtions, Chinese hamster bone marrow in vivoCBA Chromosmal aberrations, Chinese hamster bone marrow in vivo

Resulta Doseb Reference

LED/HID


(+ ) 0 0.100 Marx et al. (1983)

(+ ) 0 0.100 Marx et al. (1983)+ 0 44.~~ Sim mon (1979)?

0 56. ~~ Sim mon et al. (1979),.W

+ 0 1. ~~ Conner et al. (1983)1ti

+ 0 1.~~ Conner et al. (1983) C+ 0 1. 000 Conner et al. (1983) ~+ 0 22.() Walk et al. (1987) v-+ 0 29.~~ Walk et al. (1987)

~+ 0 34.0008 Walk et al. (1987)

+ 0 32~~ Walk et al. (1987)+ 0 22. () Walk et al. (1987)+ 0 29.000 Walk et al. (1987)+ 0 34.0008 Walk et al. (1987)

+ 0 32. ~~ Walk et al. (1987)

a+, poitive; (+ ), weakly poitive; -, negative; 0, not tested; ?, inconc1usive (variable response in several experiments within an adequate study)

hIn-vitro tests mg/ml; in-vivo tests, mg!g bw'Fanconi's anaemia (homozygotes and heterozygotes)dpanconi's anaemia (heterozygotes)

epanconi's anaemia (homozygotes and heterozygotes), ataxia telangiectasia, xerodenna pigmentosum, normalfCalculated to give 22 (F and 23 (M) mg!gBCalculated to give 34 (F and 42 (M) mg!g.Not displayed on profie

N..,.


Addition of an exogenous metabolic system was not required for genotoxic activity ofthis compound in vitro. ln bacteria, it induced prophage, DNA repair and mutation. ltinduced mutation, gene conversion and mitotic recombination in yeast and mutation Infungi. ln Drosophila melanogaster, it induced mutation and small chromosomal deletions.

1,2:3,4-Diepoxybutane induced DNA cross-links in mouse hepatocyes, dose-relatedincreases in the frequency of sister chromatid exchange in cultured CHO cells and, in a singlestudy, mutations in cultured mouse lymphoma L5 178Y cells' at the tk locus. lt induced adose-related increase in the frequency of sister chromatid exchange in cultured humanlymphocyes from normal donors and from patients with a variety of solid tumours, but notfrom Fanconi's anaemia homozygotes or heterozygotes. lt induced chromosomal aberra-tions in early-passage skin fibroblasts from Fanconi's anaemia heterozygotes, in primarylymphocyes from Fanconi's anaemia homozygotes and heterozygotes and in long-established lymphoblastoid cell lines from normal donors, Fanconi's anaemia homozygotesand heterozygotes and patients with xeroderma pigmentosum and ataxia telangiectasia.Bone-marrow cultures from Fanconi's anaemia patients and control individuals also showedincreased frequencies of chromosomal aberrations after exposure to 1,2:3,4-diepoxybutane.Chromosomal aberrations were not induced in normal lymphocyes in two studies, but smallincreases were observed in another one.

1,2:3,4-Diepoxybutane induced mutations in S. typhimurium TA1530 in the mouse host-mediated assay, but it did not induce mitotic recombination in Saccharomyces cerevisiae D3.

Significant, dose-related increases in the frequency of sister chromatid exchange wereobserved in bone marrow and in alveolar macrophages from both intact and partially hepa-tectomized mice and in the regenerating liver of hepatectomized mice. 1,2:3,4-Diepoxy-butane induced chromosomal aberrations and sister chromatid exchange in bone-marrowcells of male and female NMRI mice and ehinese hamsters exposed by inhalation or intra-peritoneal injection.

5. Summary of Data Reported and Evaluation

5.1 Exposure data

1,3-Butadiene has been produced on a large scale since the 1930s. It is used to manu-facture a wide range of polymers and copolymers, including styene-butadiene rubber, poly-butadiene, nitrile rubber, acrylonitrile-butadiene-styene resins and styene-butadienelatexes. lt Is also an intermediate in the production of various other chemicals.

Occupational exposure to 1,3-butadiene occurs in the production of monomeric 1,3-butadiene, ofbutadiene-based polymers and butadiene-derived products. The mean concen-trations reported have usually been -( 10 ppm (-( 22 mg/m3), although that level may beexceeded during sorne short-term activities. 1,3-Butadiene is not usually found at detectablelevels in the manufacture of finished rubber and plastic products. Because gasoline contains1,3-butadiene, loading of gasoline and other gasoline-related operations entail exposure to1,3-butadiene.

1,3-Butadiene has also been detected in automobile exhaust and, at levels of -( 0.02ppm (-( 0.04 mg/m3), in urban air.

1,3-BUTADIENE 273

5.2 "uman carcinogenicity data

One US cohort study of workers who manufactured 1,3-butadiene monomer showed asignificant excess risk for lymphosarcoma and reticulosarcoma. A1though there was nooverall excess risk for leukaemia, there was a suggested increase in risk in a subgroup ofworkers with 'non-routine' exposure to 1,3-butadiene.

ln a US study of workers employed in two styene-butadiene rubber plants, there was asuggested increase of risk for leukaemia with exposure to 1,3-butadiene in one of the plants.No increase in risk was seen for cancers of the lymphatic and haematopoietic system otherthan leukaemia.

ln a study of styene-butadiene rubber workers in eight plants in the USA and Canada,there was no overall increased risk for leukaemia; however, a subgroup of productionworkers had a significantly increased risk. There was no apparent increased risk for 'otherlymphatic system' cancers, although a significant risk was seen for production workers.

ln a case-control study nested within this cohort of styene-butadiene rubber workers, alarge excess of leukaemia was found which was associated with exposure to l,3-butadieneand not to styene.

ln a case-control study in the rubber industry, a large excess of lymphatic and haema-topoietic cancers, including lymphatic leukaemia, was seen among workers employed instyene-butadiene rubber production.

One study, therefore, specifically related increased risks for leukaemia to exposure to1,3-butadiene and not to styene. ln other studies, the increased risks for leukaemia andother lymphatic cancers occurred among workers whose exposure had been in the manu-facture of 1,3-butadiene or styene-butadiene rubber.

5.3 Animal carcinogenicity data

1,3-Butadiene was tested for carcinogenicity by inhalation exposure in four experimentsin mice and one in rats. Tumours were induced at aIl exposure concentrations studied,ranging from 6.25 to 8000 ppm (13.8-17 600 mg/m3). 1,3-Butadiene produced tumours atmultiple organ sites in animaIs of each sex of both species, including tumours of thehaematopoietic system and an uncommon neoplasm of the heart in male and female mice.Neoplasms at multiple organ sites were induced in mice after only 13 weeks of exposure.1,3-Butadiene induced dose-related increases in the incidence of tumours at many sites.

Two metabolites, 1,2-epoxy-3-butene and 1,2:3,4-diepoxybutane, were carcinogenic tomice and rats when administered by skin application or subcutaneous injection.

Activated K-ras oncogenes have been detected in lymphomas and in liver and lungtumours induced in mice by 1,3-butadiene.

5.4 Other relevant dataln rats, mice and monkeys, 1,3-butadiene is metabolized to an epoxide, 1,2-epoxy-

3-butene, for which quantitative differences in metabolic rates (mice :; rat:; monkey) havebeen observed. Because 1,2-epoxy-3-butene is exhaled by rats and mice exposed to

1,3-butadiene, the epoxide must undergo systemic circulation. Two experiments with hum

anliver tissue demonstrated conversion of 1,3-butadiene to 1,2-epoxy-3-butene, suggesting thathumans are not qualitatively different from animaIs in terms of epoxide formation.


Developmental toxicity, in the form of reduced fetal weight and skeletal variations, hasbeen observed in mice, but not rats, exposed by inhalation to 1,3-butadiene.

Genotoxic effects were generally observed in mice but not in rats in vivo. This apparentspecies difference was highlighted in a comparison of liver DNA adducts from the twospecies. 1,3-Butadiene induced dominant lethal effects, sperm-head abnormalities, chromo-somal aberrations, micronucleus formation and sister chromatid exchange in vivo in mice; itdid not induce micronuclei or sister chromatid exchange in rats. Unscheduled DNAsynthesiswas not induced in either rats or mice after exposure of 1,3-butadiene. The compound did notinduce mutation in the mouse lymphoma forward mutation assay and was not genotoxic toDrosophila melanogaster. It induced mutation in bacteria in the presence of an exogenousmetabolic system.

1,2-Epoxy-3-butene, one of the main metabolites of 1,3-butadiene, induced sisterchromatid exchange and chromosomal aberrations in mice in vivo and sister chromatidexchange in cultured human lymphocyes and rodent cells. It did not induce unscheduledDNA synthesis in isolated rat or mouse hepatocyes. 1,2-Epoxy-3-butene induced pointmutation in bacteria in the absence of exogenous metabolic systems. It also reacted withpurified DNA.

1,2:3,4-Diepoxybutane, another metabolite of 1,3-butadiene, induced chromosomalaberrations and sister chromatid exchange in mice and ehinese hamsters exposed in vivo. Itinduced chromosomal aberrations and sister chromatid exchange in cultured human cellsand both sister chromatid exchange and mutation in cultured mammalian cells. 1,2:3,4-Diepoxybutane induced chromosomal deletions and gene mutation in Drosophila. It wasmutagenic to bacteria in a mouse host-mediated assay as weIl as in vitro. It induced bacterialprophage and DNA repair. ln one study, it induced DNA-DNA cross-links in mouse liverDNA in vitro; it induced DNA interstrand cross-links in vitro.

5.5 Evaluationl

There is limited evidence for the carcinogenicity in humans of 1,3-butadiene.There is suffcient evidence for the carcinogenicity in experimental animaIs of 1,3-

butadiene.Studies in vitro suggest that the metabolism of 1,3-butadiene is qualitatively simIlar in

humans and experimental animaIs. 1,3-Butadiene is metabolized in mammals to epoxymeta-bolites which interact with DNA. Base-substitution mutations are induced in bacteria.Similar mutations in the K-ras oncogene have been reported in tumours induced in mice by1,3-butadiene.

Overall evaluation

1,3-Butadiene is probably carcinogenic to humans (Group lA).

lFor definition of the italicized terms, see Preamble, pp. 26-29.

1,3-BUTADIENE 275

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